WIN55,212-2 impairs non-associative recognition and spatial memory in rats via CB1 receptor stimulation.

Endogenous and exogenous cannabinoids modulate learning and memory primarily via the cannabinoid type 1 receptor (CB1R). A variety of experimental procedures has focused on the role of CB1R in various aspects of learning and memory processes. However, the picture still remains unclear as there is a lack of information on the effects of relatively low doses of CB1R agonists in relation to their effects on locomotion. The present study sought to investigate CB1R activation, using a range of relatively low doses of the CB1R agonist WIN55,212-2, on multiple aspects of learning and memory in rats. For this purpose, non-associative learning was examined using the habituation of locomotion paradigm, recognition memory was evaluated with the novel object recognition task, and the radial water maze test was selected to assess rats' spatial memory. The ability of the CB1R antagonist, SR141716A, to counteract WIN55,212-2-induced behavioral effects was also tested. WIN55,212-2 (0.3, but not 0.03 or 0.1mg/kg) disrupted non-associative learning, different aspects of short- and long-term recognition memory (storage and retrieval) and retention of spatial memory. The 0.3mg/kg dose of WIN55,212-2 also decreased ambulatory, but not vertical (rearing), activity in non-habituated rats. These effects appeared to be CB1R dependent since pretreatment with SR141716A (0.03 mg/kg) prevented the WIN55,212-2-induced behavioral effects. The present findings further support and extend the complex impact of exogenous cannabinoids on learning and memory in relation to their effects on locomotion.

In vivo occupancy of dopamine D3 receptors by antagonists produces neurochemical and behavioral effects of potential relevance to attention-deficit-hyperactivity disorder.

Dopamine D(3) receptors have eluded definitive linkage to neurologic and psychiatric disorders since their cloning over 20 years ago. We report a new method that does not employ a radiolabel for simultaneously defining in vivo receptor occupancy of D(3) and D(2) receptors in rat brain after systemic dosing using the tracer epidepride (N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-5-iodo-2,3-dimethoxybenzamide). Decreases in epidepride binding in lobule 9 of cerebellum (rich in D(3) receptors) were compared with nonspecific binding in the lateral cerebellum. The in vivo occupancy of the dopamine D(3) receptors was dose dependently increased by SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide) and U99194 (2,3-dihydro-5,6-dimethoxy- N,N-dipropyl-1H-inden-2-amine). Both antagonists increased extracellular levels of acetylcholine (ACh) in the medial prefrontal cortex of rats and modified brain-tissue levels of ACh and choline. Consistent with these findings, the D(3) receptor antagonists enhanced the acquisition of learning of rats either alone or in the presence of the norepinephrine uptake blocker reboxetine as with the attention-deficit-hyperactivity disorder (ADHD) drug methylphenidate. Like reboxetine, the D(3) receptor antagonists also prevented deficits induced by scopolamine in object recognition memory of rats. Mice in which the dopamine transporter (DAT) has been deleted exhibit hyperactivity that is normalized by compounds that are effective in the treatment of ADHD. Both D(3) receptor antagonists decreased the hyperactivity of DAT(-/-) mice without affecting the activity of wild type controls. The present findings indicate that dopamine D(3) receptor antagonists engender cognition-enhancing and hyperactivity-dampening effects. Thus, D(3) receptor blockade could be considered as a novel treatment approach for cognitive deficits and hyperactivity syndromes, including those observed in ADHD.

Δ(9)-THC and WIN55,212-2 affect brain tissue levels of excitatory amino acids in a phenotype-, compound-, dose-, and region-specific manner.

Endocannabinoids are involved in excitatory neurotransmission initiated by glutamate and aspartate. The aim of the present study was to investigate the effects of the cannabinoid agonists, Δ(9)-THC and WIN55,212-2, on tissue (prefrontal cortex, dorsal striatum, nucleus accumbens, hippocampus, amygdala and hypothalamus) levels of glutamate and aspartate in two rat phenotypes, high responders (HR) and low responders (LR), differentiated according to their response to a novel environment. HR displayed increased motor activity but no difference in basal levels of glutamate and aspartate as compared to LR. Both cannabinoids increased ambulatory activity at the low doses, this effect was observed only in HR following Δ(9)-THC, but in both HR and LR following WIN55,212-2. The cannabinoids primarily increased glutamate levels in the prefrontal cortex, dorsal striatum, nucleus accumbens and hippocampus, while the high dose of WIN55,212-2 decreased glutamate levels in the amygdala and both doses in the hypothalamus; these effects appeared overall more pronounced in HR. In contrast, the cannabinoids primarily decreased aspartate levels in all brain regions, except in the dorsal striatum, where an increase was seen after both doses of Δ(9)-THC and WIN55,212-2 as well as in the nucleus accumbens after the low dose of Δ(9)-THC in HR; these effects also appeared overall more pronounced in HR. Present results show that exogenous cannabinoids affect tissue levels of glutamate and aspartate in a phenotype-, compound-, dose-, and brain region-dependent manner.

Individual responses to novelty are associated with differences in behavioral and neurochemical profiles.

Experimental animals can be differentiated on the basis of their horizontal or vertical activity to high responders (HR) and low responders (LR) upon exposure to a novel environment. These individual differences have been associated with behavioral and neurobiological differences in a number of experimental procedures used for studying sensitivity to psychostimulants, anxiety, depression, and cognitive function. In the present study, we differentiated the rats to HR and LR based on their vertical activity upon exposure to a novel environment. Additionally, we ascertained whether HR and LR rats differ in a battery of tests such as passive avoidance (PA), object recognition (OR), and the water-maze (WM) that provide indices for cognitive function and the forced swim test (FST), an animal model of affective responsivity and antidepressant-like activity. Potential differences in neurochemical indices between the two phenotypes were also examined. HR rats displayed impaired non-spatial object recognition memory, but enhanced spatial performance, as compared to LR rats. FST induced "depressive-like" symptoms in both phenotypes that were differently manifested in HR versus LR rats. Neurochemical findings revealed distinct differences in serotonergic and dopaminergic activity in the striatum and the prefrontal cortex of HR as compared to LR rats. The above results show that HR and LR rats exhibit important differences in a battery of tests related to cognitive performance or affective responsivity, which may be associated with differences in certain neurobiological parameters.

Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine.

Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.

Identification of a high-affinity binding site involved in the transport of endocannabinoids.

Phytocannabinoids, such as the principal bioactive component of marijuana, delta9-tetrahydrocannabinol, have been used for thousands of years for medical and recreational purposes. delta9-Tetrahydrocannabinol and endogenous cannabinoids (e.g., anandamide) initiate their agonist properties by stimulating the cannabinoid family of G protein-coupled receptors (CB1 and CB2). The biosynthesis and physiology of anandamide is well understood, but its mechanism of uptake (resulting in signal termination by fatty acid amide hydrolase) has been elusive. Mounting evidence points to the existence of a specific anandamide transport protein; however, no direct evidence for this protein has been provided. Here, we use a potent, competitive small molecule inhibitor of anandamide uptake (LY2318912, IC50 7.27 +/- 0.510 nM) to identify a high-affinity, saturable anandamide transporter binding site (LY2318912; K(d) = 7.62 +/- 1.18 nM, B(max) = 31.6 +/- 1.80 fmol/mg protein) that is distinct from fatty acid amide hydrolase. Systemic administration of the inhibitor into rodents elevates anandamide levels 5-fold in the brain and demonstrates efficacy in the formalin paw-licking model of persistent pain with no obvious adverse effects on motor function. Identification of the anandamide transporter binding site resolves a missing mechanistic link in endocannabinoid signaling, and in vivo results suggest that endocannabinoid transporter antagonists may provide a strategy for positive modulation of cannabinoid receptors.

A role for cannabinoid CB1 receptors in mood and anxiety disorders.

Mood and anxiety disorders, the most prevalent of the psychiatric disorders, cause immeasurable suffering worldwide. Despite impressive advances in pharmacological therapies, improvements in efficacy and side-effect profiles are needed. The present literature review examines the role that the endocannabinoid system may play in these disorders and the potential value of targeting this system in the search for novel and improved medications. Cannabis and its major psychoactive component (-)-trans-delta9-tetrahydrocannabinol, have profound effects on mood and can modulate anxiety and mood states. Cannabinoid receptors and other protein targets in the central nervous system (CNS) that modulate endocannabinoid function have been described. The discovery of selective modulators of some of these sites that increase or decrease endocannabinoid neurotransmission, primarily through the most prominent of the cannabinoid receptors in the CNS, the CB1 receptors, combined with transgenic mouse technology, has enabled detailed investigations into the role of these CNS sites in the regulation of mood and anxiety states. Although data point to the involvement of the endocannabinoid system in anxiety states, the pharmacological evidence seems contradictory: both anxiolytic- and anxiogenic-like effects have been reported with both endocannabinoid neurotransmission enhancers and blockers. Due to advances in the development of selective compounds directed at the CB1 receptors, significant progress has been made on this target. Recent biochemical and behavioural findings have demonstrated that blockade of CB1 receptors engenders antidepressant-like neurochemical changes (increases in extracellular levels of monoamines in cortical but not subcortical brain regions) and behavioural effects consistent with antidepressant/antistress activity in rodents.

Individual responses to novelty predict qualitative differences in d-amphetamine-induced open field but not reward-related behaviors in rats.

Differences in the locomotor response of rats to a novel environment (high responders [HR] versus low responders [LR]) have been associated with differences in vulnerability to psychostimulants. In the present study we profiled extensively the behavioral repertoire of HR and LR rats (differentiated on the basis of vertical activity) during exposure to a novel environment and in response to d-amphetamine (d-amp; 1.5 mg/kg, i.p.). Moreover, we ascertained whether HR and LR rats differ in the rewarding effects of medial forebrain bundle electrical self-stimulation and in the ability of d-amp to increase the reinforcing efficacy of self-stimulation. Apart from rearing, HR animals displayed increased moving, sniffing, but decreased standing and yawning compared with LR. Factor analysis revealed a more complex behavioral structure consisting of locomotion, exploration, vertical activity and self-directed behavior for HR compared with LR rats. Qualitative, but not quantitative differences, between the two groups of rats in their behavioral responses to d-amp were found. In particular, a more complex profile mainly characterized by self-directed behavior, locomotion and vertical activity was manifested for HR as compared with LR rats. Baseline brain stimulation reward thresholds did not differ between the two groups of rats. Additionally, brain stimulation reward thresholds for the two groups were not differentially affected by d-amp. The above results suggest that HR and LR can be further differentiated upon exposure to a novel environment and in response to d-amp. This differentiation is primarily based on qualitative cohorts of their behavioral structure, but not on deviations in the reward processes as assessed by intracranial self-stimulation.

Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice.

Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post- and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2- and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2- and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.

The cannabinoid CB(1) receptor antagonist SR141716A increases norepinephrine outflow in the rat anterior hypothalamus.

The effects of the selective cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide-hydrochloride (SR141716A) on extracellular concentrations of norepinephrine and 5-hydroxytryptamine (5-HT) were assessed by in vivo microdialysis in the anterior hypothalamus of freely moving rats. SR14716A (0.3, 1, 3 mg/kg, i.p.) dose-dependently increased norepinephrine efflux to about 300% of baseline, without affecting 5-HT levels. This increase in norepinephrine outflow could play an important role in the pharmacological and potentially therapeutic actions of SR141716A.

Dopamine receptor antagonists prevent the d-amphetamine-induced increase in calcitonin gene-related peptide levels in ventral striatum.

Microdialysis in conjunction with radioimmunoassay (RIA) were used to study the effects of acute d-amphetamine or dopamine (DA) receptor antagonists administration on extracellular concentrations of calcitonin gene-related peptide (CGRP) in the ventral striatum of the rat. One hour after the subcutaneous (s.c.) injection of saline, the DA-D(1) receptor antagonist SCH 23390 (0.3 mg/kg) or the DA-D(2/3) receptor antagonist raclopride (1.0 mg/kg), one additional s.c. injection of saline or d-amphetamine (1.5 mg/kg) was given. The dialysates were collected at 60-min intervals; CGRP-like immunoreactivities (-LI) were determined by RIA. d-Amphetamine significantly increased extracellular CGRP-LI concentrations compared to the control animals. Administration of either SCH 23390 or raclopride did not significantly affect CGRP-LI concentrations. Pretreatment with either SCH 23390 or raclopride abolished the stimulatory effect of d-amphetamine on CGRP-LI levels. The results show that d-amphetamine administration results in an increase in extracellular concentrations of CGRP in the ventral striatum through a mechanism that appears to involve stimulation of either DA-D(1) or DA-D(2/3) receptors. The results also indicate that changes in dopaminergic neurotransmission affect CGRP outflow in the ventral striatum in a phasic but not tonic manner.

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.

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.

Effects of acute and chronic electroconvulsive stimuli on cAMP and cGMP efflux in the rat striatum and hippocampus.

The effects of acute and chronic electroconvulsive stimuli (ECS) on extracellular concentrations of the cyclic nucleotides, cAMP and cGMP, from the striatum and hippocampus of awake rats were studied with in vivo microdialysis in conjunction with radioimmunoassay. Acute ECS, but not acute sham-ECS, significantly increased cAMP and cGMP efflux from the striatum by about 75 and 50%, respectively. Chronic ECS did not influence significantly basal efflux of cAMP or cGMP from the striatum or the hippocampus in comparison to control animals receiving chronically sham-ECS. Administration of a challenge ECS in animals treated chronically with sham-ECS resulted in an increase in cAMP and cGMP concentrations in the striatum by 20%, but it failed to affect significantly efflux of these nucleotides in animals treated chronically with ECS. Similarly, in the hippocampus, administration of a challenge ECS in animals treated chronically with sham-ECS resulted in an increase in cAMP and cGMP concentrations by about 40 and 65%, respectively, whereas it failed to affect significantly efflux of these nucleotides in animals treated chronically with ECS. Thus, acutely administered ECS increases cAMP and cGMP efflux in the striatum and hippocampus of rats, an effect that is greatly diminished in animals chronically receiving ECS. These findings suggest changes in the cAMP and cGMP signal transduction mechanisms in response to acute and chronic ECS that may be related to the therapeutic effects of this antidepressant and antipsychotic treatment.

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.

Effects of antipsychotic drugs on cholecystokinin and preprotachykinin (substance P) mRNA expression in the rat hippocampal formation.

To assess the involvement of substance P (SP) and cholecystokinin (CCK) in the effects of antipsychotic drugs, preprotachykinin-A (PPT-A) and CCK mRNA expression was studied in the hippocampal formation using in situ hybridisation following 21 daily i.p. injections with the typical antipsychotic drug haloperidol (1 mg/kg) and the atypical drug clozapine (15 mg/kg). PPT-A mRNA levels were increased in the hippocampal CA3 subregion and in the entorhinal cortex after haloperidol, whereas a decrease was observed in the CA1 after clozapine. CCK mRNA levels increased in the CA1, the entorhinal cortex and in hilus, following both haloperidol and clozapine. It is suggested that earlier findings of increased SP levels in the hippocampal formation of schizophrenics may be a consequence of haloperidol treatment and that reduced hippocampal CCK and CCK mRNA levels found earlier in schizophrenics do not result from antipsychotic drug treatment. These results are consonant to the hypothesis that increased cortical CCK transmission may be beneficial in the treatment of psychosis.

Role of alpha7 nicotinic receptors in nicotine dependence and implications for psychiatric illness.

It has previously been shown that the reinforcing and dependence-producing properties of nicotine depend to a great extent on activation of nicotinic receptors within the ventral tegmental area (VTA), i.e. the site of origin of the mesolimbocortical dopaminergic projection. Based on the data reviewed in the present study, it is suggested that nicotine by stimulating presynaptic alpha7 nicotinic receptors within the VTA, that are probably localized on glutamatergic afferents from the medial prefrontal cortex, produces sequentially an increase in glutamate concentrations, stimulation of NMDA receptors found on dopamine (DA)-containing neurons in the VTA, enhanced firing activity of VTA-DA neurons, augmented DA release in the nerve terminal regions, and enhanced c-fos expression in the dopaminergic projection areas through activation of D1-DA receptors. In addition, it appears that alpha7 nicotinic receptors within the VTA are directly involved in nicotine-related reward and withdrawal responses. These data may be instrumental in understanding how nicotine interacts with the mesolimbocortical dopaminergic system, which is perhaps the most important component of the neural mechanisms underlying nicotine dependence. These results may also contribute to unraveling the cellular basis of nicotine's association with neuropsychiatric disorders, thereby offering the prospect of new therapeutic advances for their treatment.

Effects of atypical antipsychotic drugs on dopamine output in the shell and core of the nucleus accumbens: role of 5-HT(2A) and alpha(1)-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.