SLV330, a cannabinoid CB(1) receptor antagonist, attenuates ethanol and nicotine seeking and improves inhibitory response control in rats.

Cannabinoid CB(1) receptor (CB(1)R) signaling has been shown to play a role in the regulation of addictive behavior. In the present study, our aim was to investigate whether the CB(1)R antagonist SLV330 could reduce ethanol and nicotine self-administration and cue-induced reinstatement of ethanol and nicotine seeking behavior in Wistar rats. In operant chambers, rats were learned to emit a specific response (nose poke) in order to receive an ethanol solution or intravenous injections of nicotine. Discrete light and tone cues were presented during ethanol and nicotine delivery. These cues are particularly important for drug self-administration behavior and, through Pavlovian conditioning, acquire conditioned reinforcing and motivational properties and are therefore able to generate and maintain drug-seeking behavior. Subsequently, the CB(1)R antagonist SLV330 (doses ranging from 1 to 10mg/kg, given orally, p.o.) was administered to investigate the effects on drug self-administration. In addition, responding for ethanol and nicotine was extinguished. Then, the animals were tested for cue-induced reinstatement of ethanol and nicotine seeking and treated with vehicle or SLV330. Finally, the effects of SLV330 were studied on the number of anticipatory responses in the 5-choice serial reaction time task (5-CSRTT) in order to determine whether this compound could also increase impulse control in Wistar rats. The CB(1) antagonist SLV330 was effective in reducing ethanol self-administration at a lowest effective dose (LED) of 10mg/kg (p.o.) and reinstatement of ethanol seeking at a LED of 3mg/kg (p.o.). SLV330 was also effective in reducing nicotine self-administration and reinstatement of nicotine seeking, although at a LED of 10mg/kg (p.o.). Finally, SLV330 decreased time delay-dependent anticipatory responding (LED of 3.0mg/kg, p.o.), indicating an increased inhibitory control. These findings are in agreement with results reported with other CB(1) antagonists. The combined action of reducing the reinforcing and motivational properties of nicotine and alcohol and the improvement of impulse control supports the idea that the cannabinoid system is a promising target for anti-relapse medication.

Stimulus properties of the selective 5-HT reuptake inhibitor fluvoxamine in conditioned taste aversion procedures.

Previous attempts to train pigeons and rats to discriminate between the antidepressant fluvoxamine and its vehicle as assessed in a drug discrimination paradigm have been without success. The present experiments were, therefore, designed to assess in a conditioned taste aversion procedure (CTA) whether or not fluvoxamine possesses stimulus properties. Rats were exposed to a conditioned taste aversion (CTA) procedure. In Experiment I, subjects were given 15 mg/kg fluvoxamine p.o. or vehicle after drinking a novel tasting saccharin solution. In Experiment II, a comparison was made between the effects of 15 mg/kg fluvoxamine i.p., 30 mg/kg fluvoxamine i.p., NaCl, and lithium chloride (LiCl). In Experiment III, subjects were treated with either 10 mg/kg fluoxetine i.p., 30 mg/kg fluvoxamine i.p., or LiCl. CTA was observed after treatment with LiCl, but never after treatment with fluvoxamine or fluoxetine, suggesting that fluvoxamine does not have clear stimulus properties, which can serve as a discriminative stimulus in operant procedures. In a crossfamiliarization CTA procedure in mice, however, fluvoxamine elicited a reliable CTA, suggesting that under certain conditions (species, dose?) selective serotonin reuptake inhibitors (SSRIs) may lead to certain discriminable effects. It is as yet unclear why SSRIs apparently produce such weak and species or situation-dependent discriminable effects.

The 5-HT1A receptor agonist flesinoxan shares discriminative stimulus properties with some 5-HT2 receptor antagonists.

Ten homing pigeons were trained to discriminate the selective 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed-ratio (FR) 30 two-key operant drug discrimination procedure. The 5-HT2 receptor antagonist mianserin (ED50 = 4.8 mg/kg) fully substituted for flesinoxan, whereas ketanserin, ritanserin, mesulergine, and SB200646A substituted only partially, suggesting an interaction between 5-HT1A and 5-HT2 receptors. However, the 5-HT2 receptor agonists [DOI (0.6 mg/kg), TFMPP (10 mg/kg), mCPP (4 mg/kg)] were unable to antagonize the flesinoxan cue. The 5-HT1A receptor antagonists DU125530 (0.5-13 mg/kg) and WAY100,635 (0.1-1 mg/kg) partially antagonized the generalization of mianserin to flesinoxan. Taken together, these results are in accordance with the hypothesis that 5-HT1A receptor activation exerts an inhibitory effect on activation of 5-HT2 receptors. These results are in broad agreement with existing theories on 5-HT1A and 5-HT2 receptor interaction. Furthermore, it is argued that the discriminative stimulus properties of a drug may undergo qualitative changes with prolonged training.

The putative 5-HT1A receptor antagonist DU125530 blocks the discriminative stimulus of the 5-HT1A receptor agonist flesinoxan in pigeons.

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

The delayed-conditional-discrimination task improves measurement of working memory in rats.

The validity of delayed-matching-to-sample (DMTS) and related tasks executed in skinner boxes as an animal model for human working memory (WM) is confounded by the occurrence of mediating behaviour during delays. True matching, a supplementary task during delays and response similarity are ways to deal with this problem. However, until now rats have not been able to learn a true matching task in Skinner boxes and introduction of a supplementary task during delays does not sufficiently prevent mediating behaviour. Response similarity, on the other hand, effectively prevents the use of mediating behaviour by reducing the discriminative value of the behaviour during delays. Furthermore, it is argued that the interpretation of drug effects is confounded by baseline performance and mediating behaviour. It is shown that high baseline levels and high amounts of mediating behaviour can induce delay dependent drug effects, suggesting a specific effect on WM. We therefore assert that examination of delay-dependency of a drug effect alone is not sufficient to claim specific effects of a drug on WM. The delayed-conditional-discrimination (DCD) task uses response similarity to effectively reduce mediating behavior and does not generate high levels of baseline performance. The DCD task is therefore preferred over other tasks for the measurement of WM in rats using Skinner boxes.

Effects of cholinergic drug infusions into the dorsal part of the medial prefrontal cortex on delayed conditional discrimination performance in the rat.

Effects of bilateral infusions of cholinergic drugs into the dorsal part of the medial prefrontal cortex (dmPFC) on performance in a delayed conditional discrimination (DCD) task were examined in rats. Scopolamine dose-dependently impaired performance. No delay-dependent effect was found indicating that scopolamine did not specifically affect working memory (WM). Physostigmine alone induced a slight improvement of DCD performance independent of delay and co-administration of physostigmine with scopolamine attenuated the scopolamine-induced impairment of DCD performance. Infusion of the muscarinic M2 antagonist AQRA-471, the M3 antagonist 4-DAMP and the mixed M1-M3 antagonist UH-AH 37 did not affect performance in the DCD task, suggesting that the effect of scopolamine is not mediated by a single muscarinic receptor subtype. The results furthermore indicate that the cholinergic system in the dmPFC does not play a specific role in WM processes in the DCD task. Furthermore, the results suggest that the dmPFC cholinergic system plays a role in the attentional processes involved in the DCD task.

Effects of infusion of cholinergic drugs into the prefrontal cortex area on delayed matching to position performance in the rat.

Rats trained on a Delayed Matching To Position (DMTP) task displayed mediating behavior during delays to solve the task. Infusion of the cholinergic antagonist scopolamine into the medial Prefrontal Cortex area (mPFC), dose dependently impaired performance independent of delay. These results indicate that scopolamine does not specifically affect working memory. Infusion of the cholinesterase inhibitor physostigmine, muscarinic subtype receptor antagonists, the dopamine (D1) antagonist SCH23390, and of the GABA-A receptor antagonist bicuculline, did not affect performance in the DMTP task. In a post-hoc analysis scopolamine was found to impair discriminability in a delay-dependent manner only in animals that used mediating behavior in the majority of the trials. Furthermore, a time sampling method indicated that scopolamine infusions into the mPFC disrupted mediating behavior during the task. Results suggest that cholinergic systems in the mPFC play a role in directing attention to task relevant behavior.

Relation between stimulus discriminability and response bias in a delayed conditional discrimination task in the rat.

The present study investigated whether changes in response bias (log b) affect discriminability (log d) in a delayed conditional discrimination (DCD) task. Eight rats were trained on an DCD task and response bias was manipulated by changing the reinforcement ratio (RR) for correct responding on the two response alternatives. Three findings emerged. First, changes in RR produced changes in log b and the magnitude of these changes was related to the value of the RR. Second, log d was affected by changing RRs. Third, the effect of changes in RR on log b was larger after longer delays. These results suggest that log d and log b are not independent and it is concluded that changes in response bias (log b) may affect the discriminability measure log d. This implies that changes in log d may be mediated by changes in response bias and it is therefore recommended that log d and log b values are both reported when investigating effects of, for example, pharmacological manipulations on DCD performance.

The object delayed non-matching to sample task in rats does not depend on working memory.

Four rats were trained on an object delayed non-matching to sample task to measure working memory (WM). On separate trials a sample object was presented to the rat, which was presented again along with another object after a 3 s delay rats were rewarded with food if they chose the novel object. In this procedure the choice objects are positioned in a fixed order (the novel object was positioned at first, followed by the sample object). When the order of placement of the choice objects was reversed performance dropped from 87% to 28% correct, showing that the rats always chose the object that was first positioned into the choice area. When the order of positioning of the choice objects was randomized during training, rats were not able to learn the task. It is suggested that performance is based on a discrimination between choice objects instead of WM.

Cholinergic drug effects on a delayed conditional discrimination task in the rat.

The centrally acting cholinergic antagonist scopolamine (0.025-0.10 mg/kg ip) and the peripherally acting cholinergic antagonist methyl-scopolamine (0.01-0.10 mg/kg) dose dependently impaired discriminability independent of delay in a delayed conditional discrimination task that precludes use of mediating behavior. This indicates that scopolamine does not specifically affect working memory. Drugs that enhance cholinergic transmission neither improved discriminability nor attenuated scopolamine-induced impairments. In a post hoc analysis scopolamine was found to impair discriminability in a delay-dependent manner in rats that performed at a high level in pretest sessions. Methyl-scopolamine impaired performance independently of delay in these rats. The authors suggest that a ceiling effect at short delays produced this Drug x Delay interaction of scopolamine in the best performing rats.

Benzodiazepine receptor ligands have no specific action on working memory in a delayed conditional discrimination task in rats.

We investigated effects of benzodiazepine (BDZ) receptor ligands on working memory in a delayed conditional discrimination (DCD) task. The BDZ receptor full agonist midazolam (0.1-1.0mg/kg) dose-dependently impaired performance independent of delay, indicating no specific effect on working memory. The non-sedative BDZ receptor partial agonist bretazenil (0.06-0.6mg/kg), the inverse agonist beta-CCM (0.05-0.45mg/kg), the partial inverse agonist FG 7142 (0.5-5.0mg/kg), the antagonist flumazenil (1-10mg/kg), and the antagonist ZK 93 426 (1-10mg/kg) did not significantly affect performance. It is concluded that BDZ ligands do not affect working memory in a positively-motivated DCD task. Midazolam also impaired performance in the no-delay condition, suggesting loss of stimulus control, possibly through an attentional impairment.

Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory.

We investigated the effects of serotonergic drugs on working memory (WM) in a delayed conditional discrimination task. The 5-HT(1A) receptor full agonist flesinoxan (0.3-3.0 mg/kg) dose- and delay-dependently impaired performance, indicating a specific effect on WM. The 5-HT(1A) receptor partial agonist ipsapirone, the 5-HT( 1B/1D/2C) agonist TFMPP, the 5-HT(1A) antagonist NAN190 and the serotonin re-uptake inhibitor fluvoxamine dose-dependently impaired performance, in a delay-independent manner, indicating no specific effect on WM. The 5-HT( 2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron did not affect performance. It is suggested that the role of central serotonin receptors in WM may be restricted to 5-HT(1A) receptors.

Validity of a delayed conditional discrimination task as a model for working memory in the rat.

A delayed conditional discrimination (DCD) task in the rat was modified by requiring a response on an admission lever at the end of each delay. This requirement proved effective in precluding the use of positional cues as mediating behavior. Furthermore, validity of the procedure was assessed by examining how performance changed as a result of: length of the delay, retroactive and proactive interference, and encoding time. Results showed that log d, a measure of stimulus discriminability, decreased on longer delays (Experiment 1); decreased when an interfering stimulus was presented during delays (Experiment 2); decreased when the intertrial interval was made shorter (Experiment 3); and decreased when the sample stimuli were presented for a shorter period of time (Experiment 4). Log b, an index of bias, remained low throughout the study, indicating that no significant response bias was present. Taken together, the results support the notion that this modified DCD task is a valid model for working memory that effectively precludes the use of positional cues as mediating behavior in the rat.