Blocking Dopamine D2 Receptors Research Articles

Additive hypothermic effects of the 5-HT1A receptor agonist 8-OH-DPAT and the dopamine D2/3 receptor agonist 7-OH-DPAT in the rat.

The objective of this study was to examine possible interactions between serotonergic and dopaminergic agents lowering core temperature via stimulation of 5-HT1A and dopamine (DA) D2 receptors, respectively. The effects of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT) and the DA D2/3 receptor agonist 7-OH-DPAT on core temperature was monitored in adult male Wistar rats, approximately 300 g body weight. The temperature probe was connected to a PC-assisted temperature instrument, and an automated printer device was activated when the temperature reading had stabilized (+/-0.1 degrees C) for 10 s. As expected, 7-OH-DPAT [0.5 and 2.0 micromol x kg(-1) subcutaneous (s.c.)] as well as 8-OH-DPAT (0.15-2.4 micromol x kg(-1) s.c.), produced a dose-dependent hypothermia. When combined, there were additive effects of the two compounds, although the effects of 7-OH-DPAT were attenuated by 8-OH-DPAT at the higher doses (0.6-2.4 micromol x kg(-1)), in all probability because of emerging DA D2 receptor blocking properties of the latter compound.

Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia.

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility--T102C(3) and his452tyr(4) in the coding region and A-1438G(5) in the promoter--in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. There was a significant excess of 102C and -1438G alleles (62.7%) in the SCZ-TD-Y patients compared to SCZ-TD-N patients (41.1%) and controls (45.9%; chi(2) = 12.8, df = 2, P = 0.002; SCZ-TD-Y vs SCZ-TD-N, chi(2) = 11.4, df = 1, P = 0.0008, OR 2.41, 95% CI 1.43-3.99) and of 102CC and -1438GG genotypes (SCZ-TD-Y 42.4%, SCZ-TD-N, 16.1%, controls 20.8%, chi(2) = 13.3, df = 4, P = 0.01). The 102CC and the -1438GG genotypes were associated with significantly higher AIMS trunk dyskinesia scores (F = 3.9; df = 2, 116; P = 0.02) and more incapacitation (F = 5.0; df = 2, 115; P = 0.006). The his452tyr polymorphism showed no association with TD. These findings suggest that the 5-HT2A receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia. Previously reported association of the T102C and A-1438G polymorphisms with schizophrenia(6) may reflect association of a sub-group of patients with a susceptibility to abnormal involuntary movements related to antipsychotic drug exposure.

Dopamine-dependent inhibition of glycine release in the nucleus accumbens of the rat brain during food consumption.

Studies of Sprague-Dawley rats using in vivo intracerebral dialysis and high-performance liquid chromatography with electrochemical detection were used to investigate glycine release into the intercellular space of the nucleus accumbens during food consumption. The results showed that food consumption led to decreases in glycine levels in the intercellular space of the nucleus accumbens. Administration of the sodium channel blocker tetrodotoxin (1 microM), but not the glutamate reuptake blocker D,L-threo-hydroxyaspartate (1 mM), prevented the food-related behavior-induced decrease in glycine levels in the nucleus accumbens. Eating of food after administration of the dopamine D2 receptor blocker raclopride (10 microM) into the nucleus accumbens was accompanied by an increase in the glycine level in the intercellular space of this structure. These data provide evidence for the neural regulation of glycine release in the nucleus accumbens during food-related behavior, mediated via dopamine D2 receptors.

Chemical neuromodulation of frontal-executive functions in humans and other animals.

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.

510. Olanzapine and clozapine elevate prolactin levels after every daily dose

All antipsychotics block dopamine D2 receptors (D2R), and D2R blockade usually leads to prolactin (PRL) elevation. PRL levels in patients on both olanzapine (OLN) and clozapine (CLZ) have been shown to be similar to placebo. Most of these studies, however, are based on single-point PRL levels, usually 12–24 hours post-dose. The kinetics of PRL response has not been examined. Oxytocin: Prosocial Behavior, Social Salience, or Approach-Related Behavior?Biological PsychiatryVol. 67Issue 6PreviewWe read with much interest the article by Shamay-Tsoory and colleagues, which reported that oxytocin increases envy and gloating (1), and recent correspondence debating whether oxytocin is engaged in positive prosocial behavior (2) or increases the salience of social behaviors more generally (3). Shamay-Tsoory et al. (1) required participants to play a game of chance with another (fake participant) who either won more money (envy manipulation), lost more money (gloating manipulation), or won and lost equal amounts of money. Full-Text PDF

Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench.

Animal models are crucial for understanding the mechanism of action of antipsychotics. However, the dose of an antipsychotic in animal studies is often arbitrarily chosen, with haloperidol 1 mg/kg being a rather common standard. Recent clinical positron emission tomography (PET) studies in patients show all antipsychotics to block dopamine D2 receptors, and most are effective at doses that lead to 60% to 80% D2 occupancy. When occupancy exceeds 80%, the incidence of side effects rises sharply. To use this "bedside" information to inform the "bench," we measured D2 occupancy in rats using a method similar in principle to the [11C]-raclopride PET method in humans. We found that: 1) as in humans, haloperidol is effective in animal models of antipsychotic action when D2 occupancy > 70% and leads to effects in models of extrapyramidal side effects when D2 occupancy is > 80%; 2) very low doses, 0.06 mg/kg/sc, cause acute D2 occupancy of 75%; 3) and even doses that acutely saturate D2 receptors give little D2 occupancy after 24 hours due to the very short half-life of haloperidol in rats (2.5 hours versus 24 hours in humans). We conclude that most previous animal studies of antipsychotics have used doses giving rise to inappropriately high acute D2 occupancy and inappropriately low D2 occupancy between doses. We exemplify how this dosing confounder could lead to inappropriate conclusions. Data from the bedside translated to the bench--using D2 occupancy as a mediating variable--will lead to more valid animal models.

Dopamine Mediates Circadian Rhythms of Rod–Cone Dominance in the Japanese Quail Retina

A circadian clock modulates the functional organization of the Japanese quail retina. Under conditions of constant darkness, rods dominate electroretinogram (ERG) b-wave responses at night, and cones dominate them during the day, yielding a circadian rhythm in retinal sensitivity and rod-cone dominance. The activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, also exhibits a circadian rhythm in the retina with approximately threefold higher levels during the day than at night. The rhythm of tyrosine hydroxylase activity is opposite in phase to the circadian activity of tryptophan hydroxylase, the first enzyme in the melatonin biosynthetic pathway. We tested whether dopamine may be related to the physiological rhythms of the retina by examining the actions of pharmacological agents that effect dopamine receptors. We found that blocking dopamine D2 receptors in the retina during the day mimics the nighttime state by increasing the amplitude of the b-wave and shifting the retina to rod dominance. Conversely, activating D2 receptors at night mimics the daytime state by decreasing the amplitude of the b-wave and shifting the retina to cone dominance. A selective antagonist for D1 dopamine receptors has no effect on retinal sensitivity or rod-cone dominance. Reducing retinal dopamine partially abolishes rhythms in sensitivity and yields a rod-dominated retina regardless of the time of day. These results suggest that dopamine, under the control of a circadian oscillator, has a key role in modulating sensitivity and rod-cone dominance in the Japanese quail retina.

The non-competitive NMDA receptor blocker dizocilpine potentiates serotonergic function.

Forepaw treading induced in rats by the 5HT1A agonist 8-OH-DPAT, and head shakes caused by the administration of the 5HT2A receptor against DOI, and by the 5HT precursor (-)5HTP, were significantly increased by pretreatment with the non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine. Dizocilpine administration also significantly increased the locomotor activity induced by the serotonin agonists. The competitive NMDA receptor antagonist CGP 43487 increased only the head shakes induced by DOI, but did not alter the behavior elicited by 8-OH-DPAT, or (-)5HTP, and did not modify locomotor responses to any of the agonists used. The dizocilpine-induced potentiation of head shakes elicited by DOI and (-)5HTP was inhibited by the 5HT2 agonist ketanserin, but was not modified by the selective dopamine D1 and D2 receptor blockers SCH 23390 and (-)sulpiride. The dopamine receptor antagonists did, however, counteract the dizocilpine facilitation of both forepaw treading induced by 8-OH-DPAT, and the locomotor response to all the serotonergic agonists. The results indicate that, unlike competitive NMDA receptor antagonists, the non-competitive antagonists enhanced the expression of serotonergic stimulation, and suggest that a glutamate deficiency could contribute to the pathogenesis of schizophrenia, not only through dopaminergic, but also through serotonergic, hyperactivity.

Gynecomastia with Risperidone-Fluoxetine Combination

Gynecomastia (breast enlargement) is a side effect of neuroleptic antipsychotic drugs, related to prolactin elevation caused by dopamine D2 receptor blockade (Richelson, 1996). The atypical antipsychotic risperidone is less likely to cause gynecomastia at low doses (Casey, 1996). It can cause a dose-dependent increase in serum prolactin concentration (Peuskens, 1995), by blocking dopamine D2 receptors (Richelson, 1996). I would like to describe a patient who did not have gynecomastia with risperidone at a dose of 3 mg/day, but had it when risperidone, at a dose of 0.5 mg/day, was combined with fluoxetine. A MEDLINE search failed to find any reports about such an interaction.

Olanzapine vs placebo in the treatment of acute mania

Background: Multiple lines of evidence suggest both dopaminergic and serotonergic involvement in the reinforcing effects of cocaine. Medications such as olanzapine, which block dopamine D2 receptors, as well as serotonin receptors 5HT2A and 5HT2C may be able to reduce cocaine use in cocaine dependent patients by reducing the euphoric effects of cocaine and attenuating cocaine craving. Methods: This was a 12-week, double blind, placebo controlled, pilot trial involving 30 cocaine dependent subjects. Subjects received either olanzapine (10 mg/day) or identical placebo. Outcome measures included treatment retention, qualitative urine benzoylecgonine tests, cocaine craving, clinical global impression scores, and results from the addiction severity index. Results: Treatment retention was slightly, but significantly, better in the placebo-treated subjects. Placebo-treated subjects were more likely to be abstinent from cocaine during the trial compared to olanzapine-treated subjects, based on urine benzoylecgonine results. Olanzapine was not superior to placebo in any outcome measure. Conclusions: The results of this trial do not support the usefulness of olanzapine for the treatment of cocaine dependence. In fact, olanzapine may worsen cocaine treatment outcome.

Synapse formation and hypoxic signalling in co-cultures of rat petrosal neurones and carotid body type 1 cells.

1. To investigate synaptic mechanisms mediating chemosensory signalling in the carotid body, we developed co-cultures of chemoreceptor type 1 cell clusters and dissociated petrosal neurones (PNs) from 7- to 14-day-old rat pups and tested for functional connectivity in CO2-HCO3(-)-or Hepes-buffered medium at approximately 35 degrees C. 2. When cultured without type 1 cells, PNs were almost always quiescent (n = 104) and unresponsive to hypoxia (Po2 = 5-25 mmHg) during perforated patch, whole-cell recordings of membrane potential or voltage-activated currents; in contrast, many PNs (77 out of 170) that were juxtaposed to type 1 cell clusters in co-culture displayed spontaneous activity, comprising spikes and subthreshold potentials (SSPs) that resembled synaptic potentials. 3. Additional tests suggested that de novo chemical synapses developed between PNs and type 1 cell clusters in vitro. For example: (i) the spontaneous activity was reversibly suppressed by substituting low calcium-high magnesium in the bath; (ii) SSPs had variable amplitudes and persisted following action potential blockade with TTX (1 microM); (iii) the interval distribution between successive spontaneous events appeared random; and (iv) the frequency of spontaneous potentials was diminished (reversibly) by the nicotinic antagonist hexamethonium (100 microM), suggesting contributions from the spontaneous release of ACh. 4. Many complexes of 'juxtaposed' PNs and type 1 clusters were physiologically functional, since exposure to hypoxia caused a reversible depolarization and/or increased spike discharge in approximately 30% of such neurones (n = 140). The hypoxia-induced spike discharge persisted in the presence of the dopamine D2 receptor blocker spiperone (10-50 microM; n = 5); however, this discharge was reversibly inhibited by 100-200 microM hexamethonium, suggesting that it was mediated, at least in part, by ACh acting through nicotinic receptors. 5. The hypoxia-induced spike discharge and frequency of spontaneous potentials in co-cultured PNs were reversibly suppressed when the buffer was switched from CO2-HCO3- to Hepes (10 mM) at pH 7.4; further, 'functional' PNs that displayed spontaneous activity and/or hypoxia-induced responses in co-culture were encountered more frequently in CO2-HCO3- (> or = 40%) than in Hepes (< or = 26%) buffer. 6. We conclude that functional chemical synapses can develop de novo in cultures of carotid body type 1 cells and PNs and that ACh is probably an important excitatory neurotransmitter secreted from type 1 cells during hypoxic chemotransduction in the rat carotid body.

Impairments of movement initiation and execution induced by a blockade of dopamine D1 or D2 receptors are reversed by a blockade of N-methyl-D-aspartate receptors.

The effects of a dopamine D1 or D2 receptor blockade on initiation and execution of movements were examined using a simple reaction time task for rats. The task demands stimulus-triggered rapid initiation of locomotion to get a food reward. Time and force parameters of the transition from stance to gait were recorded allowing a detailed and separate analysis of the initiation and initial execution of locomotor initiation. Systemic administration of the preferential dopamine D2 antagonist haloperidol (0.1; 0.15 mg/kg, i.p.) caused a delayed movement initiation, as indicated by an increase in reaction time. In addition, movement execution was slowed, as measured by an increase in movement time, a decrease in the rate of development and in the maximum of the accelerative force component. Systemic administration of the selective dopamine D1 antagonist 7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (0.15 mg/kg, i.p.) induced a similar pattern of impairments as haloperidol. Dizocilpine, an antagonist of the N-methyl-D-aspartate subtype of glutamate receptors in a dose which was largely ineffective when given alone (0.08 mg/kg, i.p.) reversed impairments of movement initiation and execution that were induced by the high dose of dopamine D1 or D2 antagonists (0.15 mg/kg, i.p., respectively). It is concluded that dopamine D1 and D2 receptors are both involved in movement initiation and execution processes, which control the onset and speed of a conditioned movement, as shown here for locomotor initiation of rats. According to our results, the processes related to movement initiation and execution may be mediated by separate neuronal mechanisms, as there were no correlations between impairments of movement initiation and execution, regardless of the treatment animals received. The reversal of SCH 23390- and haloperidol-induced impairments by dizocilpine suggests a functionally antagonistic involvement of dopamine D1/D2 and N-methyl-D-aspartate receptors in the control of movement initiation and execution. The results further imply that neuroleptics blocking dopamine D1 receptors probably induce similar extrapyramidal side effects as classical neuroleptics blocking dopamine D2 receptors.

Pathophysiology of schizophrenia and the role of newer antipsychotics.

Schizophrenia is an illness with numerous neurobiologic features. It is hypothesized that patients may have a relative deficit of dopamine neurotransmission in the nigrostriatal and mesocortical tracts of the brain, as contrasted with an excess of dopamine neurotransmission in the mesolimbic area. The dopamine deficit may be related to the negative symptoms (blunted affect, anhedonia, asociality, inability to initiate and carry out complex tasks to completion) of schizophrenia, whereas the dopamine excess may be responsible for the positive symptoms (hallucinations, delusions, and thought disorder). Compared with healthy subjects, schizophrenic patients may also have increased levels of serotonin and decreased levels of norepinephrine in the brain. Conventional antipsychotic drugs nonselectively block dopamine D2 receptors throughout the central nervous system. This may help reduce positive symptoms, but has little or no effect on negative symptoms. Newer agents have more anatomically selective activity with respect to dopaminergic systems but are more complex with respect to their actions in other neurochemical systems, such as serotonin and norepinephrine, which presumably contributes to their apparent greater therapeutic efficacy.

A pharmacological, pharmacokinetic and clinical overview of risperidone, a new antipsychotic that blocks serotonin 5-HT2 and dopamine D2 receptors.

Risperidone is a benzisoxazole derivative with antipsychotic activity that is chemically unrelated to other currently available antipsychotic agents. Its neuropharmacological properties, characterized by potent central antagonism of both serotonin 5-HT2 and dopamine D2 receptors, also differ from those of most other antipsychotic drugs. The pharmacokinetics of risperidone are well understood, having been studied in healthy subjects as well as in psychotic patients. The absolute oral bioavailability of risperidone is nearly 70%, and after oral administration, it is rapidly absorbed with the plasma level reaching a peak at about 1 h. 9-Hydroxyrisperidone, one of the metabolites of risperidone, is equally active with the parent compound and so the clinical activity of a dose of risperidone is due to the combined actions of both moieties. The plasma concentrations of risperidone and its active metabolite remain dose proportional even at doses exceeding the therapeutic range. In clinical trials with chronic schizophrenia patients, risperidone has an overall therapeutic activity comparable with that of haloperidol, but at doses that produce similar improvements in the positive symptoms of schizophrenia, risperidone has a greater effect on the negative symptoms and produces less extrapyramidal side effects than does haloperidol. However, additional controlled clinical studies are needed before the claims that risperidone is therapeutically superior to haloperidol can be considered to be established firmly. Although risperidone is effective in acute schizophrenia and in non-treatment-resistant schizophrenics, studies adequately comparing risperidone with clozapine in treatment-resistant schizophrenic patients remain to be published. In addition, risperidone has been reported to be of value in patients with schizodepressive disorders. The clinical success of risperidone suggests that the development of compounds with selective affinity for 5-HT2 or other serotonin receptors may result in even further improvements in the pharmacotherapy of psychiatric disorders.

The evolution of the serotonin-dopamine antagonist concept.

Before the dopamine hypothesis of schizophrenia became established, a serotonin (5-hydroxy-tryptamine) 5-HT hypothesis was popular. This was based on the hallucinogenic properties of lysergic acid diethlyamide and abnormal serotonin levels in schizophrenics. Suggestions that serotonin might be involved in the cause of schizophrenia or could be a target for antipsychotic drug action began with the discovery that the antipsychotic agent clozapine is a potent serotonin 5-HT2A antagonist, as well as being a dopamine D2 antagonist. This led to the formulation of the serotonin-dopamine antagonist (SDA) concept for antipsychotics, with wider spectrums of activity and lower extrapyramidal side effects (EPS) liability. The principle of the SDAs is that the drug should be a potent serotonin 5-HT2A antagonist, with slightly less potent dopamine D2 receptor-blocking properties. The clinical experience with risperidone, the first member of the new class of antipsychotics, seems to offer the promise that the SDAs have significant advantages over both the conventional dopamine-blocking neuroleptics and the atypical antipsychotic clozapine. Risperidone has efficacy against both the positive and negative symptoms of schizophrenia and has a low tendency to produce EPS. Only time will tell whether other SDAs will have the same advantages.

New perspectives on biological treatment of schizophrenia

Recent research seems to indicate that many schizophrenics suffer from a defective brain development, which is reflected by basic disturbances in cognitive, information-processing, volitional and emotional functions. Positive symptoms like hallucinations and delusions may be secondary to the more basic disturbances. Varying degrees of defective brain development places a ceiling on the functional improvement that can be obtained in this illness. However, whereas positive symptoms usually respond best to neuroleptics, even negative symptoms can be improved, for instance by clozapine. To obtain such improvement, it seems necessary, in addition to blocking dopamine D2 receptors, to influence other receptor systems, as for instance serotonergic 5HT-2 and possibly dopaminergic D1 and/or D4 receptors. Stimulation of glutamatergic NMDA receptors also seems to be a promising possibility.

Dopamine D4 receptors elevated in schizophrenia.

Although the biological basis of schizophrenia is not known, possible causes include genetic defects, viruses, amines, brain structure and metabolism, neuroreceptors, and G proteins. The hypothesis of dopamine overactivity in schizophrenia is based on the fact that neuroleptics block dopamine D2 receptors in direct relation to their clinical antipsychotic potencies. Moreover, dopamine D2 or D2-like receptors are elevated in postmortem schizophrenia brain tissue. This elevation, however, is only found in vivo using [11C]methylspiperone but not [11C]raclopride. The dopamine D4 receptor gene has not yet been excluded in schizophrenia because the 21 gene variants of D4 have not yet been tested. Because the link between D1 and D2 receptors is reduced in schizophrenia tissue, we tested whether one component of this link was sensitive to guanine nucleotide. We report here that the binding of [3H]raclopride to D2 receptors in schizophrenia was not sensitive to guanine nucleotide. This finding permitted analysis of data on the binding of [3H]emonapride to the D2, D3 and D4 receptors. We conclude that the combined density of D2 and D3 receptors (labelled by [3H]raclopride) is increased by only 10% in schizophrenia brain, as found by Farde et al., but that it is the density of dopamine D4 receptors which is sixfold elevated in schizophrenia. These findings resolve the apparent discrepancy, mentioned above, wherein the density of [11C]methylspiperone-labelled sites (D2, D3 and D4), but not that of [11C]raclopride-labelled sites (D2 and D3), was found elevated in the schizophrenia striatum.

Effects of Doxapram on Carotid Chemoreceptor Activity in Newborn Kittens

Doxapram is a respiratory stimulant which acts on peripheral chemoreceptors and central respiratory neurons in a dose-dependent fashion in the adult cat. In the newborn, the mechanisms of action of doxapram are still unclear. To evaluate the effects of doxapram on the carotid chemosensory discharge and its relationship with dopaminergic mechanisms in the carotid body, two groups of kittens less than 13 days old, anesthetized, artificially ventilated and paralyzed, were prepared for the recording of a single or a few chemosensory afferents of the carotid sinus nerve. The chemosensory activity was recorded under five conditions of inspired gas mixtures (21 and 8% O2 in N2, 100% O2, 5 and 10% CO2 in O2). Group 1 (n = 9) received only doxapram and group 2 (n = 8) was pretreated with haloperidol (1 mg/kg), a dopamine D2-receptor blocker, before receiving doxapram. Doxapram significantly stimulated the discharge rate of the carotid chemoafferents under all conditions of inspired gas. The chemosensory discharge was increased by haloperidol, and was raised further after doxapram by an amount similar to group 1. For instance, in normoxia, the activity increased from 2.9 +/- 0.4 to 7.5 +/- 0.9 impulse/s (mean +/- SEM, p < 0.01) in group 1 and from 3.8 +/- 0.6 to 9.1 +/- 1.0 impulse/s (p < 0.01) in group 2. These results indicate that the mechanisms of response of carotid chemoreceptor to doxapram are developed in the newborn kitten and doxapram acts independent of the dopaminergic mechanisms in the carotid body.

Dual responses of carotid chemosensory afferents to dopamine in the newborn kitten

The effects of dopamine and of dopamine D2 receptor blocker haloperidol on the activity of carotid chemoreceptors were studied in 24 anesthetized, paralyzed and artificially ventilated newborn kittens aged 0–17 days. Single or few fiber preparations of chemoreceptors were made from one carotid sinus nerve. The responses of the chemosensory afferents to intravenous injections of dopamine (5–50 μg·kg −1) were studied in kittens breathing air and 8% O 2 in N 2. The effects of haloperidol on the chemosensory activity in air or 100% O 2 and on the chemosensory response to hypoxia were studied. Dopamine inhibited the chemosensory discharge in 25 44 studies in normoxia. Of the 9 studies performed in hypoxia, dopamine was excitatory in 5 or had no effect in 4 ( P<0.05 vs normoxia). Inhibition of the chemosensory discharge was observed in 24 37 studies performed in kittens aged more than 3 days and was predominantly excitatory in 6 7 studies in kittens aged 0–3 days ( P<0.01). One minute after haloperidol, the chemosensory discharge had increased significantly in all experiments. The biphasic pattern of chemosensory response to hypoxia (Marchal et al., Respir. Physiol. 87: 183–193, 1992) was not changed by haloperidol. The steady-state chemosensory activity was significantly increased after haloperidol, respectively from 3.9±0.7 impulses·sec −1 to 9.8±1.2 impulses·sec −1 in air, and from 13.1±1.4 impulses·sec −1 in hypoxia (mean ± SSEM, P<0.03). It is concluded that the dopaminergic mechanisms are active in the carotid body of the kitten, and the observed responses to dopamine and haloperidol are qualitatively similar to those reported in the adult cat.

Expression of the proneurotensin gene in the rat brain and its regulation by antipsychotic drugs.

In this chapter, we have presented evidence for several potential levels of interaction of NT/N gene products with dopaminergic systems of the brain. We have focused on one manifestation of this interaction related to the effects of antipsychotic drugs on expression of the NT/N gene in two anatomically discrete populations of neurons. It appears that certain antipsychotic drugs can dramatically increase expression of this gene in the dorsolateral striatum by blocking dopamine D2 receptors, perhaps by increasing expression of the gene encoding the transcriptional regulator fos. In addition, a second group of NT cells in the shell region of the nucleus accumbens also respond to these drugs by increasing NT/N gene expression. Several other peptides have been suggested to respond to treatment with antipsychotic drugs. However, there are some important differences with respect to their effects on the NT cells we have studied. The most important of these is the differential responsiveness of the DLSt and nucleus accumbens NT neurons to typical and atypical antipsychotics. We showed that all antipsychotic drugs tested increased NT/N mRNA gene expression in the accumbens, a region thought to be involved in dopaminergic disturbances underlying psychosis. However, only the typical neuroleptics that have a high propensity to induce acute extrapyramidal motor side effects influenced NT/N gene expression in the dorsolateral striatum, a structure importantly involved in regulation of motor functions. We hypothesize, therefore, that NT/N-expressing neuronal systems in the nucleus accumbens may mediate some or all of the antipsychotic effects, whereas those in the dorsolateral striatum may be involved in motor effects of neuroleptic drugs. Thus, examination of the effects of these drugs on these neuronal populations will not only clarify their mechanism of action, but in addition may provide a useful "screening" assay for new drugs with enhanced antipsychotic activity, but reduced propensity to induce the debilitating extrapyramidal side effects that are a major cause of patient noncompliance. Future studies will focus on the effects of antipsychotic drugs on NT neurons in clinically relevant models of chronic administration, and on the molecular events involved in their effects on expression of the NT/N gene in the brain.