Table 1.

Antipsychotics and Long-Term Potentiation in Animals

	Design	Outcome	Conclusions
Finn et al., 1980	-Rat hippocampal slices were perfused with 40 µM trifluoperazine -LTP was induced by delivering a tetanus	-Trifluoperazine inhibited LTP, as measured by percent change of slope of evoked potentials	-Acute administration of trifluoperazine inhibited LTP in hippocampal slices
Dunwiddie et al., 1982	-Rat hippocampal slices were treated with flupentixol (40 µM), sulpiride (100 µM), or trifluoperazine (50 µM or 100 µM) -After tetanus, population spike amplitudes were measured from area CA1	-Trifluoroperazine significantly reduced spike amplitude -Flupentixol also reduced spike amplitude, but to a lesser degree than trifluoperazine -Sulpiride did not cause change in spike amplitude	-Acute administration of trifluoperazine or flupentixol but not sulpiride inhibited LTP in hippocampal slices
Mody et al., 1984	-Rat hippocampal slices were perfused with 10 µM pimozide or 10 µM trifluoperazine during stimulation -LTP was induced by stimulating slices with a tetanus or by exposing slices to a concentrated calcium solution -Population spike amplitudes were measured from area CA1	-Pimozide and trifluoroperazine suppressed potentiation -Pimozide and trifluoroperazine did not affect potentiation when it had been established before perfusion -Similar results were seen when researchers attempted to induce potentiation by increasing calcium concentration in the bathing solution	-Acute administration of pimozide or trifluoperazine inhibited induction but not maintenance of LTP in hippocampal slices
Frey et al., 1988	-Rat hippocampal slices were perfused with the D2 antagonist domperidone (1 µM) -LTP was induced by delivering a tetanus -Domperidone was washed out after the last tetanus -Population spike amplitudes were recorded from area CA1	-Spike amplitude was lower in the domperidone group compared to control starting from the time of the third tetanus (20 min after the first) -Spike amplitude returned to baseline in the domperidone group at 8 h post-tetanus, but was still potentiated in the control group at this time	-Acute administration of domperidone inhibited LTP in hippocampal slices
Frey et al., 1990	-Rat hippocampal slices were bathed with the D1/D2 agonist apomorphine 1 µM), D1/D2 antagonist flupentixol (1 µM), or one of the D2 antagonists domperidone or sulpiride(1 µM for each) -LTP was induced by stimulating slices with a tetanus -Field EPSP and population spike amplitudes were recorded from area CA1	-Domperidone, sulpiride and fluxpenthixol impaired late LTP -Treatment with both domperidone and apomorphine together resulted in normal potentiation	-Acute administration of domperidone, sulpiride or flupentixol impaired late LTP in hippocampal slices
Jibiki et al., 1993	-Rabbits received an injection of haloperidol (0.8 mg/kg or 1.6 mg/kg) 30 min after tetanus or 1 hr before tetanus -LTP was induced by stimulating the perforant path -Field EPSP and spike amplitudes were recorded from the dentate gyrus	-When haloperidol was administered before tetanus, LTP was significantly impaired -Haloperidol administered after the tetanus showed no effect on LTP	-Acute administration of haloperidol impaired induction but not maintenance of LTP in the hippocampus
Kubota et al., 1996	-Rabbits received an injection of either 10 or 20 mg/kg of clozapine 60 min before tetanus -LTP was induced by stimulating the perforant path -Field EPSP and spike amplitudes were recorded from the dentate	-Clozapine had no effect on tetanizationem-induced LTP -In the high-clozapine group, LTP was observed following clozapine administration, before tetanization	-Acute clozapine administration without tetanization caused potentiation in the hippocampus -Tetanization after clozapine administration caused further potentiation. -Clozapine had no effect on tetanus-induced LTP
Calabresi et al., 1997	-Experiments were performed on corticostriatal slices from D2 receptor knockout mice and wild type mice. -Some wild-type slices were perfused with 1µM of L-sulpiride before stimulation. -LTP was induced by stimulating cortical fibers	-Wild type slices in the presence of magnesium showed LTD in response to stimulation, whereas slices from D2R null mice showed LTP.	-Mouse corticostriatal slices lacking D2 receptors showed LTP in response to tetanization, whereas wild-type slices showed LTD.
Kubota et al., 2000	-Rabbits received injections of the NMDA receptor antagonist MK-801 (0.5 mg/kg or 1.0 mg/kg), while 5 control animals received injections of vehicle only -30 min later, both groups were given clozapine (20 mg/kg) -60 min after clozapine injections, LTP was induced by stimulating the perforant path	-In the control condition, clozapine caused potentiation. Tetanization caused further potentiation -0.5 mg/kg of MK-801 had no effect on clozapine- and tetanus-induced potentiation -1.0 mg/kg of MK-801 blocked clozapine-induced and tetanus-induced potentiation	-A high concentration of NMDA antagonist impaired clozapine-and tetanization-induced LTP in rabbit hippocampus
Kubota et al., 2001	-Rabbits received an injection of risperidone (0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg), or saline 60 min before tetanus -LTP was induced by stimulating the perforant path -Field EPSP and spike amplitudes were recorded from the dentate gyrus	-There was apparent dose-dependent suppression of LTP as indexed by spike amplitudes and EPSP slopes	-Acute administration of risperidone inhibited LTP in rabbit hippocampus
Kubota et al., 2002	-Rabbits received an injection of zotepine (1.0 mg/kg, 2.0 mg/kg, 5.0 mg/kg), or saline (5 in each group) 60 min before tetanus -LTP was induced by stimulating the perforant path -Field EPSP and spike amplitudes were recorded from the dentate	-There was apparent dose-dependent suppression of LTP as indexed by spike amplitudes and EPSP slopes	-Acute administration of zotepine inhibited LTP in rabbit hippocampus
Gemperle et al. 2003	-Rat prelimbic cortex slices were perfused with clozapine (10 µM), haloperidol (0.2 µM), or iloperidone (2.5 µM) -LTP was induced by stimulating slices in layer II -Field EPSP and spike amplitudes were recorded from layer V of the prelimbic cortex	-Clozapine facilitated synaptic potentiation, increasing the duration of potentiation -Haloperidol had no effect on LTP, while iloperidone impaired it	-Acute administration of clozapine facilitated, iloperidone impaired and haloperidol had no effect on LTP in rat prelimbic cortex slices
Centonze et al., 2004	-Rats received either acute (1 injection) or chronic (20 injections) haloperidol (1 mg/kg). Slices were tested in a solution of 1.2 mMol Mg to induce LTD or an Mg-free solution to induce LTP. -Wild-type mice and mice lacking the long and short isoforms, or only the long isoform of the D2 receptor were also tested in 1.2 mM or 0 mM of Mg. -LTP was induced with high-frequency stimulation delivered to the excitatory terminals in corticostriatal slices -Motor coordination and behavior were assessed.	-In rats, HFS in the Mg-free solution induced LTP, whereas in 1.2 mM Mg it induced LTD. Acute haloperidol treatment had no effect,whereas chronic haloperidol treatment prior to stimulation resulted in LTP in both the 1.2 mMol Mg and the Mg-free solutions. -Wild-type and all mutant mice displayed LTP when stimulated in the absence of Mg. Chronic haloperidol treatment enhanced LTP amplitude in wild-type but not mutant mice. -Stimulation in the presence of Mg resulted in LTD in wild-type mice but LTP in mutants. There were no significant motor or behavioral effects	-Chronic but not acute administration of haloperidol enhanced LTP in corticostriatal slices in a magnesium-free solution by signaling through long isoform D2 receptors
Gemperle and Olpe, 2004	-Rats were administered either acute (1 dose) or chronic (21 doses) of clozapine through drinking water, with the target dose being 30 mg/kg per day -LTP was induced by stimulating layer II of rat prelimbic cortex slices -Field potentials and spike amplitudes were recorded from layer V of the prelimbic cortex	-LTP was impaired, though still present, in the chronic clozapine condition. The difference was only significant in the 50–60 minute post-tetanus period -No difference was observed between control and acute groups	-Chronic administration of clozapine mildly impaired LTP in rat prelimbic cortex -Acute clozapine had no effect
Matsumoto et al., 2008	-Rats were administered 20 mg/kg clozapine or 1 mg/kg haloperidol, as well as 10 µg of either D1 agonist SKF-38393, D1 antagonist SCH23390 or D2 antagonist remoxipride 20 min before tetanization -LTP was induced by two series of HFS of hippocampal area CA1, in-vivo -Population spike amplitude were recorded from medial PFC	-Haloperidol did not affect LTP while clozapine facilitated it. Clozapine-induced potentiation was not observed -The potentiating effect of clozapine was blocked by the D1 receptor antagonist but not by the D2 receptor antagonist -The effect of the D1 agonist on LTP was similar to that of clozapine -Clozapine caused a sustained increase in dopamine level, while tetanization caused a transient increase	-Acute administration of clozapine facilitated LTP through D1 receptor signaling in rat hippocampus. -Haloperidol had no effect on LTP.
Kubota et al., 2008	-One group of rabbits received an injection of clozapine (20 mg/kg) and tetanic stimulation 60 min later, another received clozapine but no tetanic stimulation and a third received tetanic stimulation but no clozapine -LTP was induced by stimulating the perforant path -EPSPs and population spikes were recorded for the duration of the experiment -Extracellular dopamine and 5-HT were measured every 5 min with microdialysis	-In the control, there was no change in extracellular dopamine or 5-HT after tentanization -There was an increase in extracellular dopamine for 60 min following clozapine injection -Tetanization did not significantly affect dopamine level -Neither clozapine injection nor tetanic stimulation affected extracellular 5-HT	-Acute administration of clozapine increased extracellular dopamine but not 5-HT. -Tetanization had no effect on dopamine or 5-HT.
Abe et al., 2009a	-Rats received injections of saline, chlorpromazine (10, 30 or 100 nmol), or haloperidol (4.4 nmol or 13.3 nmol) -Another group of rats underwent either sham surgery or basolateral amygdala lesion and received chlorpromazine (100 nmol) or saline. -A third group of rats underwent either sham surgery or ventral tegmental lesion, and received injections of a D1 agonist or D2 agonist to the basolateral amygdala. -In all experiments, after the intervention, LTP was induced with high frequency stimulation of perforant path -Population spike amplitude was measured from the granule cell layer of the basal ganglia	-Injection of chlorpromazine and haloperidol suppressed LTP in dose-dependent manner -The inhibitory effect of 4.4 nmol of haloperidol was not seen when animals were injected with 3 nmol of D2 agonist quinpirole -Basolateral amygdala lesioned group had impaired LTP. There was no additional impairment due to chlorpromazine. -Haloperidol suppressed LTP in the sham group at 4.4 nmol and 13.3 nmol -Ventral tegmental lesion suppressed LTP, and the injection of aD1 or D2 agonist rescued LTP	-Acute administration of haloperidol suppressed LTP in the basal ganglia by antagonizing D2 receptors. -Dopaminergic transmission from basolateral amygdala enables LTP in the basal ganglia. -Dopaminergic transmission from ventral tegmentum through both D1 and D2 receptors inputs enables LTP in the basal ganglia.
Abe et al, 2009b	-Rats received introcerebral ventricular administration of saline, chlorpromazine (15 nmol), GABAA antagonist picrotoxin (1mg/kg) or D2 agonist quinpirole (80 nmol) -LTP was induced with either a strong tetanus of 100 pulses at 100 Hz delivered twice 30 s apart or a weak tetanus of 100 pulses at 100 Hz, once -Experimenters stimulated the basolateral amygdala and recorded from the dentate gyrus	-The strong tetanus, but not the weak, induced LTP -Chlorpromazine suppressed LTP after strong tetanic stimulation -When picrotoxin was injected with chlorpromazine no suppression was seen -The injection of either quinpirole or picrotoxin allowed weak stimulation to induce LTP -There was no additive effect when quinpirole and picrotoxin were administered together	-Impairment of hippocampal LTP by chlorpromazine was prevented when GABAergic inhibition was blocked
Molina-Luna et al., 2009	-Experiments were performed on rat cortical slices from area M1 -Slices were bathed with D2 antagonist raclopride or D1 antagonist SCH23390 -LTP was induced with theta burst stimulation -For behavioural experiments, rats performed a motor learning task involving reaching with forlimbs after receiving an injection of raclopride, sulpiride, D1 antagonist SCH23390 or vehicle. Some animals received sulpiride only after task acquisition.	-LTP was significantly impaired by raclopride and SCH23390 -In slices bathed in either antagonist, LTP was still present, although weaker in amplitude -Raclopride, sulpiride and SCH23390 injected in M1 forelimb area during the learning phase of the reaching task lowered success rate -Sulpiride injected after the reaching task had been learned did not affect success rate	-Acute administration of a D2 or D1 antagonist impaired LTP in cortical slices from area M1. -D1 and D2 antagonists impaired skill acquisition of a motor learning task. -After the task had been learned, a D2 antagonist had no effect on performance.
Xu et al., 2009	-Cortical slices from anterior cingulate cortex and/or prelimbic cortex from wild type and dopamine transporter knock-out mice were treated with bath application of haloperidol (10 µM) -LTP was induced with either theta-burst stimulation, tetanic stimulation or paired stimulation -Stimuli were applied to layer II/III of the anterior cingulate or prelimbic cortices and recordings were taken from layer V -In-vivo experiments were performed with wild-type and dopamine transporter knock-out mice that received IP injections of haloperidol (acute dose 1 mg/kg or chronic 0.5mg/kg/day for 14 days), raclopride (3 mg/kg), clozapine (acute dose 6 mg/kg or chronic 4mg/kg/day for 14 days) -In-vivo, LTP was induced using theta burst stimulation with recording electrodes implanted in the right PFC	-For all three induction protocols, LTP was impaired in the knock-out mice compared to controls -Bathing dopamine transporter knockout slices in haloperidol restored LTP -In in-vivo experiments a single haloperidol injection increased potentiation in mutants, however it was not restored to the level of wild type animals. Acute haloperidol had no effect on prefrontal LTP in wild type mice. -Similar effects were seen with acute raclopride and clozapine -Chronic exposure to haloperidol or clozapine fully restored LTP in knock-out mice.	-LTP is impaired in hyperdomapinergic conditions. This impairment is partially reversed by acute haloperidol, raclopride or clozapine but not by D1 blockade. -Chronic treatment with clozapine or haloperidol fully restored LTP in hyperdopaminergic conditions.
Delotterie et al., 2010	-STOP null mice received risperidone in drinking water (0.1 or 0.3 mg/kg/day) or clozapine (1 or 3 mg/kg/day) injected intraperitoneally for four weeks -Four behavioural tests were performed: Y maze test, social investigation test, marble burying test, forced swim test -LTP was investigated in hippocampusof knockout or control animals who had been administered either clozapine (IP injection of either 3 or 10 mg/kg/day) or risperidone -LTP was induced by theta burst stimulation	-STOP null mice were impaired on all behavioral tests. Deficits on the social investigation test as well as some cognitive deficits were alleviated by chronic risperidone or clozapine. -STOP null mice showed impairments in LTP compared to wild type -High clozapine dose significantly improved LTP in knockout mice, but low dose did not -Risperidone did not improve LTP	-Chronic administration of clozapine, but not risperidone, reversed the LTP impairment seen in STOP null mice
Xu and Yao, 2010	-Mouse PFC slices were bathed in dopamine (100 µM) and/or haloperidol (2 µM), D2 agonist quinpirole (10 µM) -LTP was induced by paired stimulation -Prefrontal corex slices were stimulated in layer II/III and EPSPs were recorded from layer V pyramidal neurons	-Paired stimulation did not induce LTP in controls but did induce LTP in slices bathed in dopamine -Administering haloperidol with dopamine abolished LTP -Quinpirole had a similar effect to dopamine on LTP induction	-Dopaminergic transmission through D2 receptors enables LTP induction in mouse PFC slices. -Acute administration of haloperidol impaired LTP
Shim et al., 2012	-Rats were administered olanzapine (1–2 mg/100 g body weight daily for 4 weeks) in water or lithium in rat chow -LTP was induced by tetanic stimulation to slices from area CA1 of rats	-Lithium facilitated LTP for over 60 min -Olanzapine facilitated LTP for first 10 min following tetanization. The effect diminished over time until there was no difference from control after 50 min	-Chronic administration of olanzapine facilitated LTP for 10 min after tetanization in rat hippocampal slices

Abbreviations: EPSP – excitatory post-synaptic potential, GABA – gamma-Aminobutyric acid, LTD – long-term depression, LTP – long term potentiation, NMDA – N-methyl-D-aspartate, PFC – prefrontal cortex, STOP - Stable tubule-only polypeptide