Biomedical subjects

T H Svensson

Publications and source records attributed to T H Svensson.

At least 19 recordsLinked to original sources

PubMed2004

Nitric oxide is involved in nicotine-induced burst firing of rat ventral tegmental area dopamine neurons.

In the present study, using single cell recordings in vivo and intracellular recordings in vitro from midbrain slices, the role of N-methyl-d-aspartate (NMDA) receptor signaling on firing activity in ventral tegmental area dopamine neurons elicited by nicotine was investigated in the rat. In accordance with previous studies, systemic nicotine (0.5 mg/kg s.c.) increased both firing rate and burst firing of dopamine neurons in vivo, and bath-applied nicotine (10 microM) increased firing rate in vitro. The competitive NMDA receptor antagonist CGP39551 (2.5 mg/kg i.p.) inhibited nicotine's effects on burst firing and also attenuated the nicotine-induced increase in firing rate. Moreover, although the nitric oxide (NO)-synthase inhibitor N-nitro-l-arginine-methyl-ester (l-NAME; 5.0 mg/kg i.p.) had no effect on cell firing by itself, it prevented the response to nicotine in vivo. In contrast, l-NAME (100 microM) did not influence nicotine's effect on dopamine cell firing in vitro, suggesting that the effect of l-NAME seen in vivo is dependent on presynaptic afferent input. The present study confirms previous results suggesting that the effect of systemically administered nicotine is in part presynaptic and mediated via NMDA receptors. The data also indicate that NO plays an important role in the previously demonstrated, indirect, glutamate-mediated excitation of these neurons by nicotine. By inference, our results provide additional support for the involvement of NO in nicotine dependence.

2-Amino-5-phosphonovalerate↗

PubMed2003

Selective noradrenaline reuptake inhibition enhances serotonergic neuronal activity and transmitter release in the rat forebrain.

Present pharmacotherapy of major depression is, in principle, based on enhancement of central monoaminergic neurotransmission. Clinical studies utilizing depletion experiments indicate that antidepressants which primarily enhance serotonergic or noradrenergic central activity, i.e. serotonin or nor-adrenaline reuptake inhibitors, largely work by two separate neuronal pathways. However, experimental studies have shown that noradrenaline may regulate serotonergic neurotransmission both at the serotonin cell body and nerve-terminal level. We therefore investigated the effects of the selective NRI reboxetine on serotonergic neuronal activity and extracellular levels of transmitter in the nerve-terminal area. In vivo electrophysiological experiments showed that low doses of reboxetine significantly enhance the firing rate of serotonergic neurons in the dorsal raphe nucleus of anaesthetized rats. Also, in the medial prefrontal cortex reboxetine (3 mg/kg s.c.) enhanced, whereas citalopram (3 mg/kg s.c.) reduced, extracellular concentrations of serotonin measured by means of microdialysis in awake rats, using a low dose of citalopram (0,5 micro M) in the perfusion solution. Local administration of reboxetine only induced an increase in cortical serotonin levels at very high concentrations (1000 micro M). Hence, NRIs may cause a secondary enhancement of central serotonergic activity by a mechanism separate from 5-HT reuptake inhibition; an effect that may contribute to their clinical antidepressant efficacy.

Adrenergic Uptake Inhibitors↗

PubMed2002

Biochemical effects in brain of low doses of haloperidol are qualitatively similar to those of high doses.

Typical and atypical antipsychotic drugs (APD) show differential effects in brain on both dopamine output and activation of Fos-like immunoreactivity (FLI) in dopamine nerve terminal regions. Typical APD increase dopamine output preferentially in the core and atypical APD increase dopamine output preferentially in the shell of the nucleus accumbens (NAC). Whereas both typical and atypical APD increase FLI in NAC, typicals cause FLI activation in the striatum and atypicals cause FLI activation in the prefrontal cortex. Clinically, low doses of haloperidol cause less side-effects than higher doses, and low-dose haloperidol has been suggested as a cost-effective alternative to atypical APD. Here, in vivo voltammetry in anaesthetised, pargyline-pretreated rats was used to measure dopamine output in the two subdivisions of the NAC and, in addition, immunohistochemistry was used to assess FLI activation in dopamine target areas, following acute haloperidol administration. Haloperidol, 0.001 and 0.01 mg/kg i.v., caused a significantly higher dopamine output in the core than in the shell of the NAC. Moreover, haloperidol 0.05 and 0.5, but not 0.005, mg/kg s.c. increased FLI in the NAC and the striatum, but not in the medial prefrontal cortex. Thus, even extremely low doses of haloperidol generate, in principle, the same biochemical effects in brain as higher doses, and these effects remain different from those of atypical APD. These biological data indicate that clinical differences between haloperidol and atypicals are qualitative rather than dose-dependent. Consequently, our results do not support the use of low-dose haloperidol as replacement for atypical APD in the treatment of schizophrenia.

Amygdala↗

PubMed2002

Active immunization against nicotine suppresses nicotine-induced dopamine release in the rat nucleus accumbens shell.

BACKGROUND: Tobacco smoking is the largest preventable cause of morbidity and premature mortality in the world. Although its medical consequences are well documented, 20-50% of the population even in developed countries remain tobacco smokers. The drugs presently used in smoking cessation have limited efficiency and, therefore, there is a need for alternative and improved treatments. One novel approach in this regard may be provided by immunization against nicotine. OBJECTIVE: The present study in male Wistar rats investigated if active immunization with a novel nicotine immunogen, IP18-KLH, may generate nicotine-selective antibodies and, furthermore, whether this treatment might prevent nicotine from exerting its stimulating effect on the mesolimbic, dopaminergic reward system in the brain. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to determine the titer of nicotine antibodies in plasma after immunization with IP18-KLH in Freund's adjuvant. Competitive ELISA was used to assess the selectivity of the antibodies. Finally, we used in vivo voltammetry to investigate whether active immunization with IP18-KLH could prevent nicotine-induced dopamine release in the shell of nucleus accumbens (NAC(shell)). RESULTS: The present study shows that active immunization with IP18-KLH generates antibodies that are highly selective for nicotine. Furthermore, immunization with IP18-KLH prevented the nicotine-induced increase in dopamine release in the NAC(shell), a biochemical correlate to the rewarding properties of nicotine. CONCLUSIONS: Active immunization with IP18-KLH prevents a central effect of nicotine that is considered critical for the induction of nicotine dependence. Consequently, active immunization may provide long-term protection against initiation of tobacco dependence, an effect that may prove particularly advantageous in relapse prevention.

Animals↗

PubMed2002

Active immunization against nicotine prevents reinstatement of nicotine-seeking behavior in rats.

BACKGROUND: The presently available pharmaceutical aids in smoking cessation possess a rather limited effectiveness. Therefore, we have synthesized a series of immunoconjugates that stimulate the induction of antibodies which may bind nicotine in the blood, thereby preventing it from passing the blood-brain barrier. Thus, the reinforcing action of nicotine in the brain, which is the driving force in tobacco smoking, should be abolished. OBJECTIVE: The present study was undertaken to test this notion in a long-term relapse model in rats, measuring the reinstatement of nicotine-seeking behavior, following active immunization with IP18-KLH, one of our immunoconjugates. METHODS: Male Wistar rats were immunized with a nicotine-KLH conjugate (nicotine immunogen) and Freund's adjuvant after having been trained to meet the criteria of stable nicotine self-administration on a fixed ratio (FR3) schedule. The rats were subsequently extinguished from nicotine self-administration behavior and finally, as extinction was completed, they were exposed to small, priming doses of nicotine, which previously have been shown to reinstate the nicotine-seeking behavior. The antibody titers were measured by ELISA. RESULTS: It was found that rats with high titers (>1:10,000) of antibodies against nicotine, in contrast to those with low/no nicotine selective antibodies, do not reinstate nicotine self-administration behavior when they are exposed to nicotine. CONCLUSIONS: Our findings indicate that active immunization against nicotine may effectively abolish the reinforcing action of nicotine in brain, an effect which is critical for relapse in nicotine dependence. These data suggest the potential utility of active immunization in smoking cessation programs.

Animals↗

PubMed2001

Catalepsy induced by the 5-HT(1A) receptor antagonist WAY 100635 in rats pretreated with the selective serotonin reuptake inhibitor citalopram.

Neither a high dose of the selective serotonin reuptake inhibitor citalopram (100 micromol kg(-1) s.c.), nor the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCl (WAY 100635) (0.1--0.4 micromol kg(-1) s.c.) produced any evidence of catalepsy in adult male rats. When combined with citalopram, however, WAY 100635 produced a dose-dependent, and statistically significant, catalepsy in the inclined grid test.

Animals↗

PubMed2001

Receptor-mediated regulation of serotonin output in the rat dorsal raphe nucleus: effects of risperidone.

OBJECTIVES: The present study was undertaken to characterize the regulation of serotonin (5-HT) efflux and neuronal activity in the dorsal raphe nucleus (DRN) as well as to examine the potential ability of the antipsychotic drug risperidone to interfere with these mechanisms. METHODS AND RESULTS: By using microdialysis in freely moving rats, it was found that administration of the alpha2 adrenoceptor antagonist idazoxan (0.25 mg/kg, SC), the 5-HT1B/D receptor antagonist GR 127,935 (1.0 mg/kg, SC) and risperidone (0.6 or 2.0 mg/kg, SC) increased 5-HT output in the DRN. Local DRN perfusion with GR 127,935 or risperidone via reversed dialysis (100 or 10-100 microM, respectively) enhanced 5-HT efflux in this area, whereas idazoxan (10-100 microM) failed to affect this parameter. Both systemic administration and reversed DRN dialysis of the D2/3 and 5-HT2A receptor antagonists raclopride (2.0 mg/kg, SC or 10-100 microM) and MDL 100,907 (1.0 mg/kg, SC or 10-100 microM), respectively, were without effect. Intraraphe dialysis of the 5-HT1B/D receptor agonist CP 135,807 (0.2 microM) decreased the efflux of 5-HT in the DRN, an effect which was antagonized by co-administration of either GR 127,935 or risperidone (10 and 3.3 microM, respectively). By using single-cell recording, it was found that administration of GR 127,935 (50-400 microg/kg, IV) decreased, whereas CP 135,807 (2.5-20 microg/kg, IV) increased firing of 5-HT cells in the DRN. CONCLUSIONS: Our findings suggest a regulatory role of local 5-HT1B/D receptors on 5-HT efflux as well as cell firing in the DRN and indicate that risperidone may interfere with the regulation of 5-HT availability in this area primarily via blockade of 5-HT1D receptors.

Animals↗

PubMed2001

Effects of competitive and non-competitive NMDA receptor antagonists on dopamine output in the shell and core subdivisions of the nucleus accumbens.

The effects of acute intravenous administration of the non-competitive NMDA receptor antagonists, phencyclidine (PCP), dizocilpine (MK-801; (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,b)cyclohepten-5,10-imine), and the competitive NMDA receptor antagonist CGP 39551 (DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid) on extracellular dopamine concentrations were analyzed in the shell and core subdivisions of the nucleus accumbens (NAC), associated with limbic and motor functions, respectively. Extracellular dopamine concentrations were assessed utilizing differential normal pulse voltammetry in chloral hydrate anesthetized, pargyline pretreated rats. Intravenous administration of PCP (0.5 mg/kg) or MK-801 (0.1 mg/kg) both significantly elevated extracellular dopamine levels in the NAC shell but not in the core. However, administration of relatively low doses of the competitive NMDA receptor antagonist CGP 39551 (2.5 mg/kg) failed to affect dopamine output in either region. However, when a higher dose (10 mg/kg) was administered a significant elevation in dopamine output was obtained in the shell compared to the core. Our data demonstrate that non-competitive NMDA receptor antagonists evoke an accumbal dopamine output that is selective to limbic cortical related NAC regions. This profile is shared also by competitive NMDA receptor antagonists when given in high, but not low doses. Our results are compatible with the reported elicitation of PCP-like behavioral effects by competitive NMDA receptor antagonists when administered in relatively high doses. Moreover, these findings suggest that differences in the regional accumbal dopamine output between competitive and non-competitive NMDA receptor antagonists may be essentially attributable to the relative degree of NMDA receptor antagonism achieved by the drugs. This experimental model may afford a biochemical means to assess the psychotomimetic liability of NMDA receptor antagonists, a side effect that may reduce their usefulness as neuroprotective agents.

2-Amino-5-phosphonovalerate↗

PubMed2001

Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex.

Central dopaminergic neurons have been suggested to be involved in the pathophysiology of several psychiatric disorders, including depression, and appear to be modulated by noradrenergic activity both at the nerve terminal level and at the somatodendritic level. In recent years reboxetine, a selective noradrenaline reuptake inhibitor that differs from tricyclic antidepressants by its low affinity for muscarinic, cholinergic and alpha(1)-adrenergic receptors, has been introduced clinically. In the present study the effect of reboxetine on the function of the mesolimbocortical dopamine system was investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clinically relevant plasma concentrations. Reboxetine (0.625--20 mg/kg intravenously) induced an increase in burst firing, but not in average firing frequency of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, reboxetine (0.15--13.5 mg/kg intraperitoneally) caused a significantly enhanced DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 microM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local administration of reboxetine into the VTA (333 microM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of VTA DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation.

Adrenergic Uptake Inhibitors↗

PubMed2000

Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area.

We have previously provided evidence that the stimulatory action of systemic nicotine on dopamine release in the rat nucleus accumbens is initiated in the ventral tegmental area (VTA), and that it appears to be mediated partly through an indirect, presynaptic mechanism. Thus, it was found that blockade of N-methyl-D-aspartate (NMDA) receptors in the VTA attenuates the enhancing effect of nicotine on extracellular levels of dopamine in the nucleus accumbens. Moreover, the nicotine-induced dopamine output in the nucleus accumbens was found to be blocked by pretreatment with methyllycaconitine (MLA) in the VTA, indicating a role for alpha7* nicotinic acetylcholine receptors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in the VTA through stimulation of alpha7* nAChRs localized on excitatory amino acid (EAA)ergic afferents. To test this hypothesis, we here measured extracellular concentrations of glutamate and aspartate in the VTA in response to systemic nicotine, with or without concurrent infusion of MLA in the VTA, using microdialysis in anaesthetized rats. Since the medial prefrontal cortex is an important source of EAA input to the VTA, we also assessed the density of alpha-bungarotoxin binding sites in the VTA in rats lesioned bilaterally in the prefrontal cortex with ibotenic acid and in sham-lesioned rats by means of quantitative autoradiography. Nicotine (0.5 mg/kg, s.c.) significantly increased extracellular levels of both aspartate and glutamate in the VTA. MLA (0.3 mM) infused locally in the VTA prevented the nicotine-induced increase in glutamate and aspartate levels. Ibotenic acid lesions of the prefrontal cortex decreased the density of alpha-bungarotoxin binding sites in the VTA by about 30%. These data indicate that nicotine increases the extracellular levels of excitatory amino acids in the VTA through stimulation of nAChRs in the VTA and that part of the alpha7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex.

Animals↗

PubMed2000

Nicotine-induced Fos expression in the nucleus accumbens and the medial prefrontal cortex of the rat: role of nicotinic and NMDA receptors in the ventral tegmental area.

We have previously shown that the nicotine-induced dopamine release in the nucleus accumbens can be attenuated by local administration into the ventral tegmental area (VTA), of antagonists at nicotinic and N-methyl-D-aspartate (NMDA), but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. In the present study, we investigated the role of nicotinic and NMDA receptors in the VTA for the expression of Fos-like immunoreactivity (FLI) in the shell and core of the nucleus accumbens and in the medial prefrontal cortex (mPFC) of the rat after acute nicotine administration. Systemically administered nicotine increased FLI in both the mPFC and the nucleus accumbens when compared to saline controls, although this effect was more pronounced, and reached statistical significance in the nucleus accumbens, especially in the core region. When mecamylamine was delivered by reverse dialysis into the VTA, the systemic nicotine-induced FLI was significantly attenuated in the nucleus accumbens. Similarly, the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5), infused locally in the VTA, also antagonized the nicotine-induced FLI in the nucleus accumbens. Neither mecamylamine nor AP-5 alone affected basal FLI levels in any of the structures studied. Local administration of nicotine in the VTA increased FLI in the nucleus accumbens but not in the mPFC. Since the nicotine-induced FLI is probably due to an increased dopamine release in both the nucleus accumbens and the mPFC, we conclude that FLI in the nucleus accumbens is mediated, to a large extent, through the activation of dopamine neurons via nicotinic and NMDA receptors in the VTA, whereas the nicotine-induced FLI in the mPFC is subjected to a differential control mechanism, tentatively involving nicotinic receptors at the terminal level of the mPFC-projecting dopamine neurons.

2-Amino-5-phosphonovalerate↗

PubMed2000

Selective c-fos induction and decreased dopamine release in the central nucleus of amygdala in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.

In the present study the neuronal expression of Fos, the protein product of c-fos, was used to study changes in neuronal activity in nerve terminal regions of the ascending dopaminergic system during nicotine withdrawal. Rats were infused for 14 days with nicotine (9 mg/kg/day nicotine hydrogen tartrate) via minipumps, whereas control animals carried empty pumps. Withdrawal was induced by the nicotinic receptor (nAChR) antagonist mecamylamine (1 mg/kg, s.c.). The behavior of each animal was observed after mecamylamine injection and subsequently its brain was processed for Fos-like immunoreactivity. Following mecamylamine, the score of abstinence signs increased in the nicotine-treated rats as compared to controls. The number of Fos-positive nuclei was substantially increased in the central nucleus of amygdala (CNA) in animals undergoing mecamylamine-precipitated withdrawal, whereas no significant changes in c-fos expression were observed in the basolateral amygdaloid nucleus, the core and the shell of the nucleus accumbens, the dorsolateral striatum, or the medial prefrontal cortex. Since there are indications of involvement of amygdaloid dopaminergic neurotransmission in anxiety-a core symptom of withdrawal from dependence-producing drugs-in a second experiment utilizing microdialysis we examined whether nicotine withdrawal affects dopaminergic neurotransmission in the CNA. Following mecamylamine injection, dopamine (DA) significantly decreased in nicotine-treated animals compared with controls. These results indicate that the mecamylamine-precipitated nicotine withdrawal reaction is accompanied by a selective induction of c-fos and a concurrent decrease in DA release in the CNA, which may have a bearing on symptoms such as anxiety and distress, which frequently are associated with the nicotine abstinence reaction in humans.

Amygdala↗

PubMed2000

Nicotine-induced excitation of midbrain dopamine neurons in vitro involves ionotropic glutamate receptor activation.

Presynaptic nicotinic acetylcholine receptors (nAChR) on glutamatergic as well as GABAergic synaptic terminals are considered to play a major role in mediating nicotinic effects on neurons in many parts of the brain. However, to what extent the excitatory effect of nicotine on the dopamine (DA) neurons in the ventral tegmental area (VTA) is mediated via their glutamatergic input remains unclear. The excitatory effect of nicotine on these cells was therefore studied by means of intracellular recordings from a midbrain slice preparation in the presence of antagonists to NMDA and non-NMDA receptors and compared to the effect of nicotine alone. Our results show that the excitatory effect of nicotine is markedly reduced both in the presence of 2-amino-5-phosphonopentanoic acid (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), i.e., from 115 +/- 14.3% to 63.4 +/- 11.0% and 63.2 +/- 13.6%, respectively. The coapplication of both antagonists did not have an additional effect in reducing the nicotine-induced increase in firing frequency. These findings clearly indicate that ionotropic glutamate receptor activation partly, but not entirely, mediates the excitatory effect of nicotine on DA neurons in VTA. In addition, we have pharmacologically characterized the nicotinic effect by the use of different nAChR antagonists, i.e., dihydro-beta-erythroidine (DHBE), mecamylamine, and methyllycaconitine (MLA). DHBE and mecamylamine but not MLA completely blocked the effect of nicotine, indicating that nAChRs other than alpha(7)-subtype are involved in the nicotine-induced excitation of the dopamine neurons in the brain slice preparation.

2-Amino-5-phosphonovalerate↗

PubMed2000

Partial 5-HT1A receptor agonist properties of (-)pindolol in combination with citalopram on serotonergic dorsal raphe cell firing in vivo.

RATIONALE: Pindolol has been reported to shorten the onset of antidepressant action of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) as well as to increase their efficacy. It has been postulated that pindolol enhances the antidepressant effect of SSRIs by blocking somatodendritic 5-HT1A autoreceptors, thus antagonizing the SSRI-induced feedback inhibition of midbrain 5-HT cell firing. A recent study, however, found that pindolol suppresses the firing rate of central 5-HT cells, suggesting that the compound possesses agonistic activity at 5-HT1A autoreceptors. OBJECTIVES: The purpose of the present study was to investigate if acute administration of (-)pindolol antagonizes the decrease in firing rate of dorsal raphe 5-HT cells produced by acute treatment with the SSRI citalopram. METHODS: Extracellular recordings of single 5-HT neurons in the dorsal raphe nucleus in anaesthetized rats. RESULTS: Administration of 0.25 or 3.0 mg/kg (IV) (-)pindolol alone decreased the firing rate of a majority of the 5-HT cells studied, an effect that was reversed by the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg, IV). Neither 0.25 nor 3.0 mg/kg (-)pindolol reversed the citalopram (0.1-0.2 mg/kg. IV)-induced suppression of 5-HT cell activity, but produced a further decrease in firing rate. In contrast, WAY100635 (0.1 mg/kg) completely reversed this effect of citalopram. Yet, pretreatment with 3.0, but not 0.25 mg/kg (-)pindolol significantly attenuated the acute inhibitory effect of citalopram on serotonergic cell firing. CONCLUSIONS: The present findings support the previous notion that (-)pindolol possesses prominent agonistic activity at somatodendritic 5-HT1A autoreceptors, but also indicate that it may possess a weak antagonistic action at these receptors.

Animals↗

PubMed2000

Enhancement of antipsychotic-like effects by combined treatment with the alpha1-adrenoceptor antagonist prazosin and the dopamine D2 receptor antagonist raclopride in rats.

Blockade of central alpha1-adrenoceptors has been implicated as a possible factor contributing to the atypical antipsychotic profile of clozapine. Thus, in the present study we examined the effects of concomitant alpha1-adrenoceptor and dopamine D2 receptor blockade on conditioned avoidance response performance, as an index of antipsychotic-like activity, and on the induction of catalepsy, as a test for extrapyramidal side effect liability, in rats. It was found that pretreatment with the alpha1-adrenoceptor antagonist prazosin (0.2mg kg(-1) s.c.) caused an enhancement of a suppression of conditioned avoidance response in the presence of the dopamine D2 receptor antagonist raclopride (0.05-0.20 mg kg(-1) s.c.). The effect was most prominent at a subthreshold dose of raclopride (0.05 mg kg(-1)). At these doses, prazosin or raclopride by themselves, or in combination, did not produce catalepsy. In addition, pretreatment with prazosin (0.2mgkg(-1) s.c.) did not alter the catalepsy produced by a higher dose of raclopride (1.0 mg kg(-1) s.c.). It is suggested that, in the presence of low dopamine D2 receptor occupancy, additional alpha1-adrenoceptor blockade might improve antipsychotic efficacy, and thereby improve the therapeutic window with regard to parkinsonism.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2000

Intraaccumbal mecamylamine infusion does not affect dopamine output in the nucleus accumbens of chronically nicotine-treated rats.

Recently we have shown that the nicotinic receptor (nAChR) antagonist mecamylamine both when administered systemically and locally into the ventral tegmental area (VTA) to chronically nicotine-treated rats reduces dopamine (DA) output in the nucleus accumbens (NAC) and elicits behavioral withdrawal signs. However, the putative contributory role of nAChRs in the NAC in mediating these effects of systemic mecamylamine has not been clarified. Therefore, we here investigated the effect on extracellular levels of DA in the NAC of local intraaccumbal administration of mecamylamine to chronically nicotine-treated rats and its putative behavioral correlates. In these experiments local application of mecamylamine into the NAC, in a concentration that increased NAC DA levels in control rats, did not affect DA output or behavior in the nicotine-treated animals. These results provide further support for the contention that nAChRs in the VTA, but not in the NAC, are of major importance for the mesolimbic DA reduction and associated behavioral signs in nicotine withdrawal.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Atypical antipsychotic-like effect of AMPA receptor antagonists in the rat.

Systemic administration of two chemically different AMPA receptor antagonists, GYKI52466, 20mg/kg, and LY326325, 18mg/kg, given subcutaneously, caused a selective suppression of conditioned avoidance response in the rat with preservation of escape behavior. The number of intertrial crosses was not affected and no catalepsy was observed. These experimental results indicate, in principle, an antipsychotic effect of AMPA receptor antagonists with a low liability for extrapyramidal side effects and, consequently, a pharmacological profile consonant with atypical antipsychotic drugs.

Animals↗

PubMed2000

Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs.

Clinical studies utilizing imaging techniques demonstrate that classical antipsychotic drugs, such as haloperidol, in clinically effective doses display around 75% dopamine (DA)-D(2) receptor occupancy in the brain. In contrast, the atypical antipsychotic drug clozapine is even more effective at only about 45% D(2)-receptor occupancy. Yet at this D(2)-receptor occupancy classical antipsychotics are not effective, raising the question of which other receptors may be involved in mediating the atypical antipsychotic profile of clozapine and other atypical antipsychotics. The present paper describes experimental work aimed at elucidating this critical question, utilizing the phencyclidine (PCP) model of schizophrenia in combination with studies of typical and atypical antipsychotics as well as various specific receptor blocking agents. Both electrophysiological methods, i.e. single cell recording from DA neurons in the ventral tegmental area (VTA), and biochemical analysis of biogenic amines such as DA following microdialysis in difference DA terminal areas in the brain, were used. In addition, behavioural measurements using the conditioned avoidance response (CAR) paradigm and assessments of locomotor activity were utilized. Experiments with functional inactivation of the medial frontal cortex (mPFC) in the rat as well as with MK-801 and other antagonists at central NMDA-receptors revealed that following systemic administration of schizophrenomimetic NMDA-receptor antagonists a profound dysregulation of the mesocorticolimbic DA system occurs, severely impairing the dynamic physiological response range of the neurons. Specifically, DA neurons which largely project to the mPFC showed a profound loss of burst firing, whereas VTA-DA neurons, which mainly project subcortically, showed an increased monotonous high-frequency firing with increased DA output from nerve terminals and concomitant behavioural activation. Significantly, drugs with a prominent 5-HT(2A)-receptor blocking action could effectively restore the burst firing mode, i.e. phasic responsivity, in mesocortically projecting DA neurons, and also potentiate the CAR suppressant effect of the selective D(2)/D(3)-receptor antagonist raclopride without increasing catalepsy scores. The selective alpha(1)-adrenoreceptor antagonist prazosin effectively suppressed both the stereotyped, high-frequency firing of subcortically projecting DA neurons following systemic MK-801 and the concomitant behavioural, i.e. locomotor, activation. In addition, the MK-801 evoked DA release in the nucleus accumbens was suppressed. A similar effect was seen also with AMPA-receptor antagonists when applied locally into the VTA and, in addition, systemic administration of chemically different AMPA-receptor antagonists caused a CAR-suppressant effect similar to both classical and atypical antipsychotic drugs. These results and other data showing a clearcut difference between typical and atypical antipsychotic drugs on DA output in the shell and core, respectively, of the nucleus accumbens, suggest that both the 5-HT(2A)- and the alpha(1)-adrenoreceptor blocking effects of a number of atypical antipsychotic drugs in all probability contribute to their antipsychotic effect. Moreover, our results indicate that AMPA-receptor antagonists may possess an atypical antipsychotic profile.

Animals↗