Monica M. Marcus

Mode of Action of Atypical Neuroleptics in Relation to the Phencyclidine Model of Schizophrenia: Role of 5-HT2 Receptor and α1-Adrenoreceptor Antagonism

&NA; In experiments in rats, by the use of single‐cell recordings from midbrain dopamine (DA) neurons of the ventral tegmental area (VTA), the systemic administration of the schizophrenomimetic N‐ methyl‐D‐aspartate receptor antagonists phencyclidine (PCP) or dizocilpine (MK‐801) caused an increased firing rate but reduced the variability of firing in VTA DA neurons. Burst firing was increased in cells predominantly located in the paranigral nucleus, a subdivision of the VTA largely projecting to the nucleus accumbens and other limbic regions, but reduced in DA cells predominantly located in the parabrachial pigmented nucleus, another subdivision of the VTA that projects largely to the prefrontal cortex (PFC). Thus, a severely impaired signal‐to‐noise ratio within the PFC DA projection was obtained, concomitant with an overactive mesolimbic DA system. The administration of high doses of ritanserin or atypical neuroleptics with prominent serotonin (5‐hydroxytrypyamine) 5‐HT2 receptor antagonist action, such as clozapine or amperozide, produced preferential activation of the PFC DA projection. In contrast, the selective D2 receptor antagonist raclopride caused a greater activation of the subcortical than cortical DA projections, as assessed by microdialysis experiments in vivo from our laboratory. Adding ritanserin treatment to raclopride markedly enhanced the raclopride‐induced increase in DA levels in the medial PFC, an effect probably mediated by augmentation of the raclopride‐induced increase in the burst firing of mesocortical DA neurons, but failed to affect the action of raclopride on striatal DA levels. In addition, ritanserin alone preferentially increased extracellular concentrations of DA in the shell subdivision of the nucleus accumbens that is closely linked to the limbic system, as assessed by in vivo voltammetry. However, the PCP‐ or MK‐801‐induced increased burst firing within the mesolimbic DA projection, which is probably causally related to the hyperlocomotion induced by these drugs in low doses, was significantly inhibited by the administration of the &agr;1‐adrenoceptor antagonist prazosin. Like high but not low doses of raclopride, prazosin also antagonized the behavioral stimulation induced by the systemic administration of MK‐801 in rats. Thus, atypical antipsychotic drugs such as clozapine and amperozide with high affinity for 5‐HT2 receptors and relatively high affinity for &agr;1‐adrenoceptors can, by 5‐HT2 blockade, preferentially activate and improve DA signaling in the mesocortical DA projection after distortion by drugs such as PCP. At the same time, these drugs may antagonize a hyperactive mesolimbic DA system not only postsynaptically through D2 antagonism, but also presynaptically through their &agr;1‐adrenoceptor‐blocking properties.

Differential effects of acute and chronic nicotine on dopamine output in the core and shell of the rat nucleus accumbens

SummaryLike several drugs of abuse, nicotine increases dopamine (DA) release in the nucleus accumbens (NAC). In the present study, the effects of acute and chronic nicotine on DA output in two subdivisions of the NAC, the core and the shell, which are largely associated with motor control and limbic functions, respectively, were examined by means of in vivo differential normal pulse voltammetry in anesthetized, pargyline-treated rats.In the first experiment, acute administration of nicotine (25, 50 and 100 μg/ kg, cumulative doses; i.v.) was found to increase DA levels in the NACshell to 163% of baseline, whereas DA output in the NACcore was not significantly affected. In the second experiment, animals were pretreated with twelve daily injections of saline or nicotine (0.5 mg/kg, i.p.); about 24 hours after the last injection, the animals were challenged with nicotine (50μg/kg and 100 μg/kg, cumulative doses; i.V.). Under these conditions, nicotine increased DA output in the NACshell in saline-pretreated animals to 248% and in nicotine-pretreated rats to 180%. Also, nicotine increased DA output in the NACcore in saline-pretreated animals to 185%, whereas no significant effect was observed in nicotine-pretreated rats.The results of the present experiments indicate (i) that acutely administered nicotine or nicotine challenge in chronically pretreated animals with either saline or nicotine consistently increases DA release to a greater extent in the NACshell than in the NACcore, and (ii) that chronic nicotine pretreatment reduces the stimulatory action of nicotine on DA output in either the shell or the core subdivision of the NAC.

Ritanserin potentiates the stimulatory effects of raclopride on neuronal activity and dopamine release selectively in the mesolimbic dopaminergic system

The atypical profile of clozapine and some other new atypical antipsychotic drugs has been attributed to a relatively selective effect on the mesolimbic dopaminergic system, as well as to their potent serotonin 5-HT2 receptor antagonism and high ratio of 5-HT2 to dopamine D2 receptor affinities. It is unclear, however, how concurrent 5-HT2 and D2 receptor antagonism specifically affects the mesoaccumbens and the mesocortical dopaminergic systems.The present study examined the effect of pretreatment with the 5-HT2 receptor antagonist, ritanserin, on changes in midbrain dopamine neuronal activity as well as in forebrain, extracellular concentrations of dopamine, induced by relatively low doses of the D2 receptor antagonist raclopride, utilizing in vivo extracellular single cell recording techniques and voltammetry in anesthetized rats, as well as microdialysis in freely moving rats. Raclopride alone (10–2560 μg/kg, i.v.) induced a dose-dependent increase in three parameters of neuronal activity, i.e. burst firing, firing rate and variation coefficient, of midbrain DA neurons. This effect of raclopride was more pronounced in cells of the ventral tegmental area than in cells of the substantia nigra-zona compacta. Ritanserin alone (1.0 mg/kg, i.v.) also increased all three parameters of neuronal activity in dopamine cells of the ventral tegmental area, but only firing rate in the cells of the substantia nigra. Ritanserin pretreatment (30 min) significantly enhanced the stimulatory effects of low doses of raclopride (10–20 μg/kg) on burst firing in dopamine neurons, preferentially in the ventral tegmental area. Raclopride alone (50 μg/kg, s.c.) increased extracellular concentrations of dopamine in the medial prefrontal cortex and the dorsolateral striatum by 75 and 110%, respectively, as measured by microdialysis. Ritanserin alone (1.5 mg/kg, s.c.) did not significantly affect cortical and striatal extracellular dopamine concentrations; however, pretreatment (40 min) with ritanserin elevated the raclopride-induced increase of dopamine concentrations in the medial prefrontal cortex to about 250%, but failed to affect the action of raclopride on striatal dopamine levels. Raclopride alone (10 and 320 μg/kg, i.v.) dose-dependently increased extracellular concentrations of dopamine in the nucleus accumbens and the dorsolateral striatum to about 500%, as determined by voltammetry. Ritanserin alone (1.0 mg/kg, i.v.) did not significantly affect the voltammetric dopamine signal in the nucleus accumbens or the dorsolateral striatum; however, ritanserin pretreatment (30 min) enhanced the raclopride-induced increase in accumbal but not striatal dopamine concentrations to about 1600%. The stimulatory effect of the combined ritanserin plus raclopride treatment on neuronal activity and DA release was more pronounced in the mesolimbic than the nigrostriatal dopaminergic system.The present data indicate that concurrent 5-HT2 and D2 receptor antagonism selectively affects the activity of the mesolimbic dopaminergic system. These findings provide an experimental basis for the notion that combined 5-HT2 and D2 receptor antagonism may underlie the limbic mode of action of at least some atypical antipsychotic drugs and consequently contribute to their unique therapeutic effects.

Combined α2 and D2/3 receptor blockade enhances cortical glutamatergic transmission and reverses cognitive impairment in the rat

The alpha(2) adrenoceptor antagonist idazoxan enhances antipsychotic efficacy of classical dopamine D(2) antagonists in treatment-resistant schizophrenia. The mechanisms are not fully understood, but we have previously shown that the combination of idazoxan with the D(2/3) receptor antagonist raclopride, similarly to clozapine but not classical antipsychotic drugs, augments dopamine efflux in the prefrontal cortex, and also generates an enhanced suppression of the conditioned avoidance response. We have now investigated the effects of clozapine, raclopride, idazoxan and the combination of raclopride and idazoxan on (i) electrically evoked excitatory post-synaptic potentials and currents in pyramidal cells of the rat medial prefrontal cortex, using intracellular electrophysiological recording in vitro, (ii) the impaired cognitive function induced by the selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801, using the 8-arm radial maze test, (iii) the in-vivo D2, alpha(2A) and alpha(2C) receptor occupancies of these pharmacological treatments, using ex-vivo autoradiography. Whereas neither idazoxan nor raclopride alone had any effect, the combination exerted the same facilitation of glutamatergic transmission in rat prefrontal pyramidal neurons as clozapine, and this effect was found to be mediated by dopamine acting at D(1) receptors. Similarly to clozapine, the combination of idazoxan and raclopride also completely reversed the working-memory impairment in rats induced by MK-801. Moreover, these effects of the two treatment regimes were obtained at similar occupancies at D(2), alpha(2A) and alpha(2C) receptors respectively. Our results provide novel neurobiological and behavioural support for a pro-cognitive effect of adjunctive use of idazoxan with antipsychotic drugs that lack appreciable alpha(2) adrenoceptor-blocking properties, and define presynaptic alpha(2) adrenoceptors as major targets in antipsychotic drug development.

Differential actions of typical and atypical antipsychotic drugs on dopamine release in the core and shell of the nucleus accumbens

The effects of acute administration of typical and atypical antipsychotic drugs on extracellular dopamine (DA) concentrations in brain were examined in two subdivisions of the nucleus accumbens (NAC), the core and the shell, which are largely associated with motor control and limbic functions, respectively, by using in vivo differential normal pulse voltammetry in anesthetized, pargyline pretreated rats. The following drugs were studied: haloperidol (0.1 and 1.0 mg/kg), clozapine (1.0 and 5.0 mg/kg), amperozide (1.0 and 2.0 mg/kg), risperidone (0.1 and 1.0 mg/kg), the selective 5-HT2A/5-HT2C receptor antagonist ritanserin (1 mg/kg) and the selective DA-D2/D3 receptor antagonist raclopride (10 and 320 micrograms/kg). Drugs with predominantly high 5-HT2 receptor antagonistic action, such as amperozide and ritanserin, as well as low doses of either risperidone or clozapine increased DA concentrations to a greater extent in the shell than in the core subdivision of the NAC. In contrast, drugs with a more potent D2 receptor antagonistic action, such as haloperidol and raclopride, as well as high doses of either risperidone or clozapine, elicited a larger DA increase in the core than in the shell. Consequently, atypical antipsychotics characterized by potent 5-HT2 receptor antagonism can be differentiated from typical antipsychotic drugs on the basis of their preferential effect on DA transmission in the shell region of the NAC.

Adjunctive α2-adrenoceptor blockade enhances the antipsychotic-like effect of risperidone and facilitates cortical dopaminergic and glutamatergic, NMDA receptor-mediated transmission

Compared to both first- and second-generation antipsychotic drugs (APDs), clozapine shows superior efficacy in treatment-resistant schizophrenia. In contrast to most APDs clozapine possesses high affinity for alpha2-adrenoceptors, and clinical and preclinical studies provide evidence that the alpha2-adrenoceptor antagonist idazoxan enhances the antipsychotic efficacy of typical D2 receptor antagonists as well as olanzapine. Risperidone has lower affinity for alpha2-adrenoceptors than clozapine but higher than most other APDs. Here we examined, in rats, the effects of adding idazoxan to risperidone on antipsychotic effect using the conditioned avoidance response (CAR) test, extrapyramidal side-effect (EPS) liability using the catalepsy test, brain dopamine efflux using in-vivo microdialysis in freely moving animals, cortical N-methyl-D-aspartate (NMDA) receptor-mediated transmission using intracellular electrophysiological recording in vitro, and ex-vivo autoradiography to assess the in-vivo alpha2A- and alpha2C-adrenoceptor occupancies by risperidone. The dose of risperidone needed for antipsychotic effect in the CAR test was approximately 0.4 mg/kg, which produced 11% and 17% in-vivo receptor occupancy at alpha2A- and alpha2C-adrenoceptors, respectively. Addition of idazoxan (1.5 mg/kg) to a low dose of risperidone (0.25 mg/kg) enhanced the suppression of CAR, but did not enhance catalepsy. Both cortical dopamine release and NMDA receptor-mediated responses were enhanced. These data propose that the therapeutic effect of risperidone in schizophrenia can be enhanced and its EPS liability reduced by adjunctive treatment with an alpha2-adrenoceptor antagonist, and generally support the notion that the potent alpha2-adrenoceptor antagonistic action of clozapine may be highly important for its unique efficacy in schizophrenia.

Prazosin modulates the changes in firing pattern and transmitter release induced by raclopride in the mesolimbic, but not in the nigrostriatal dopaminergic system

Most antipsychotic drugs are, in addition to being dopamine (DA) D2 receptor antagonists, also relatively potent α1 adrenoceptor antagonists. Here, we have studied the effects of the selective DA D2 receptor antagonist raclopride, alone and in combination with the selective α1 adrenoceptor antagonist, prazosin, on midbrain DA neurons utilizing extracellular single cell recording techniques. As a reference compound, haloperidol (0.05–1.6 mg/kg, i.v.), a potent antagonist at both DA D2 receptors and α1 adrenoceptors, was included in the electrophysiological part of the study. In addition, in vivo voltammetry was used to measure extracellular DA concentrations in the nucleus accumbens (NAC) and the dorsolateral striatum (STR) in anesthetized, pargyline pretreated rats treated with the above drugs. Raclopride (10–5120 μg/kg, i.v.) induced a dose dependent increase in firing rate of DA neurons in the ventral tegmental area (VTA), that was significant already at 10 μg/kg, and in the substantia nigra-zone compacta (SN-ZC), that reached significance at 2560 μg/kg. Burst firing of DA neurons was also increased in the VTA at 40 μg/kg, as well as in the SN-ZC at 640μg/kg. A low dose of raclopride (80 μg/kg, cumulated dose) induced a significant increase in extracellular DA concentrations in NAC to 490% and in STR to 220%. A high dose of raclopride (2560 μg/kg, cumulated dose) induced a 930% increase in extracellular DA concentrations in NAC, but only a 280% increase in STR. These data demonstrate that raclopride exerts a relatively selective action on mesolimbic DA neurons. Prazosin (0.3 mg/kg, i.v.) decreased burst firing of VTA, but not SN-ZC DA neurons. Pretreatment with prazosin (15 min) significantly enhanced the increase in firing rate of VTA-DA neurons caused by raclopride within the 20–160 μg/kg dose range. The effects of the pretreatment on raclopride-induced burst firing, on the other hand, was a marked decrease in VTA-DA neurons, while it left the effect of raclopride on SN-ZC DA neurons unaffected. Pretreatment with prazosin also caused a reduction in the raclopride-induced elevation of extracellular DA concentrations in the NAC, but not in the STR. This effect was only seen with the high dose of raclopride (2560 μg/kg). Although haloperidol increased both firing rate and burst firing of neurons in VTA and SN-ZC, the haloperidol-induced increase in burst firing appeared much smaller than that caused by raclopride. Thus, α1 adrenoceptors seem to modulate the effects of DA D2 receptor antagonism preferentially in the mesolimbic DA system.

Nicotine hapten structure, antibody selectivity and effect relationships: Results from a nicotine vaccine screening procedure

The aim of the present study was to synthesise and screen a set of novel nicotine hapten immunogens used for the treatment of nicotine dependence. In the screening process we studied the amount of antibodies generated and their selectivity, using ELISA techniques, and their effects on nicotine-induced dopamine release in the NAC(shell) of the rat, assessed by in vivo voltammetry. We conclude that even small changes such as the linker attachment on the nicotine molecule as well as the structure of the linker may greatly influence the selectivity of the antibodies and the central neurobiological effects of nicotine that are considered critical for its dependence producing properties.

Effects of S-citalopram, citalopram, and R-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N-methyl-D-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat.

Escitalopram, the S‐enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R‐citalopram antagonizes this positive allosteric modulation. Escitaloprams effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R‐citalopram on dopamine cell firing in the ventral tegmental area, using single‐cell recording in vivo and on NMDA receptor‐mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40–640 μg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80–1280 μg/kg) had no effect on firing rate and only increased burst firing at high dosage. R‐citalopram (40–640 μg/kg) had no significant effects. R‐citalopram (320 μg/kg) antagonized the effects of escitalopram (320 μg/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R‐citalopram (5 nM), potentiated NMDA‐induced currents in pyramidal neurons. Escitaloprams effect was antagonized by R‐citalopram and blocked by the dopamine D1 receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor‐mediated neurotransmission may have bearing on its cognitive‐enhancing effect and superior efficacy compared to other SSRIs in major depression. Synapse, 2010.

Effects of atypical antipsychotic drugs on dopamine output in the shell and core of the nucleus accumbens: role of 5-HT2A and α1-adrenoceptor antagonism

The effects of acute intravenous administration of several new, atypical antipsychotic drugs (APDs): olanzapine (0.05 and 1.0 mg/kg), sertindole (0.1 and 1.0 mg/kg) and quetiapine (0.25 and 2.5 mg/kg), a selective 5-HT(2A) receptor antagonist, M100907 (0.03 and 0.3 mg/kg), and an alpha(1)-adrenoceptor antagonist, prazosin (0.3 mg/kg), on regional dopamine output were examined in the two subdivisions of the nucleus accumbens (NAC), the core and shell, which seem associated with motor control and limbic functions, respectively, by using in vivo differential normal pulse voltammetry in anaesthetised, pargyline-pretreated rats. Both quetiapine and sertindole, in the two doses used, caused a more pronounced dopamine release in the shell than in the core region of the NAC. In contrast, the low dose of olanzapine increased dopamine output almost to the same extent in both regions, whereas the high dose increased dopamine output to a greater extent in the core. M100907 selectively increased dopamine output in the shell. Also, prazosin significantly increased dopamine output in the shell, but not in the core. The results indicate that both 5-HT(2A) and alpha(1)-adrenoceptor antagonism may play an important role in the preferential effect of atypical APDs on dopamine output in the shell versus the core of the NAC.