Sarah M. Turgeon

The delayed effects of phencyclidine (PCP) disrupt latent inhibition in a conditioned taste aversion paradigm

The acute effects of a low dose of phencyclidine (PCP) and the delayed effects of a high dose of PCP on latent inhibition (LI) were assessed in a series of experiments using conditioned taste aversion paradigms. Each paradigm involved a preexposure phase in which water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE), followed by a conditioning phase in which animals were allowed access to sucrose and subsequently injected with the negative reinforcer lithium chloride, and a test phase in which animals were allowed access to both sucrose and water. LI was assessed by comparing the %-sucrose consumed in PE and NPE groups on the test day. The effects of low-dose PCP (2.5 mg/kg) were assessed by comparing LI in animals treated with vehicle or PCP 15 min prior to the onset of the preexposure and conditioning phases. A 4-day paradigm involved 2 days of preexposure followed by a day of conditioning and a test day. This paradigm produced comparable levels of LI in vehicle and PCP-treated animals. A 5-day extinction paradigm involved 2 days of preexposure followed by 2 days of conditioning and a test day. This paradigm abolished LI in vehicle and PCP-treated animals. A 3-day paradigm involved 1 day of preexposure followed by a day of conditioning and a test day. One day of preexposure induced a modified LI effect in both in vehicle and PCP-treated animals. The delayed effects of high dose PCP (8.6 mg/kg) were assessed by comparing LI in animals treated with vehicle or PCP 20 h prior to the onset of the preexposure and conditioning phases in the 4-day paradigm. PCP disrupted latent inhibition in this paradigm. The results are discussed in the context of their relevance to the ability for PCP to model schizophrenic symptomatology.

Prior exposure to phencyclidine decreases voluntary sucrose consumption and operant performance for food reward.

Prior exposure to the psychotomimetic drug phencyclidine (PCP) produces a number of schizophrenia-like behaviors in animals. The goal of the present study was to determine whether prior exposure to PCP produces decreased reward function, thereby modeling one aspect of negative schizophrenic symptomatology. To this aim, the consequences of prior exposure to PCP were assessed on two types of appetitive consumptive behavior. In the first set of experiments, the effects of PCP (15 mg/kg, 20 h before testing) on sucrose consumption were tested for three consecutive days under conditions of deprivation and nondeprivation. In the deprivation condition, animals were water deprived for 4 h prior to injection of PCP or saline (SAL). Twenty hours following the injection (24 h after the onset of water deprivation), animals were allowed access to either 5% sucrose or water for 30 min. In the nondeprivation condition, 5% sucrose consumption was measured for 30 min, 20 h after PCP or SAL injection and water consumption was measured during the 23.5 h preceding sucrose consumption. PCP decreased both sucrose and water consumption under deprivation conditions on the second and third day of testing but selectively decreased sucrose consumption under nondeprivation conditions on all three testing days. LiCl (50 mg/kg, 20 h before testing) did not significantly reduce sucrose consumption in the nondeprivation paradigm, indicating that the effect of PCP was not due to conditioned taste aversion. In the second experiment, PCP (15 mg/kg, 20 h before testing) decreased operant performance when animals were switched from a continuous reinforcement schedule of food delivery to a fixed ratio (FR4) schedule. Apomorphine (APO, 30 microg/kg, 30 min before testing), a positive control, induced a similar performance deficit. However, the PCP-induced deficit was not apparent until the third day of FR4 testing while the APO deficit was apparent on the first day. The effects of PCP on sucrose consumption demonstrate PCP-induced decreases in reward function. However, the delayed appearance of the PCP-induced decrease in operant performance suggests that these results may be better explained by a PCP-induced attentional deficit, also characteristic of schizophrenic psychopathology.

The delayed effects of DTG and MK-801 on latent inhibition in a conditioned taste-aversion paradigm.

The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801-induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. Published by Elsevier Science Inc., 2000

Decreased striatal c-Fos accompanies latent inhibition in a conditioned taste aversion paradigm.

Latent inhibition (LI) is a phenomenon whereby previous exposure to a stimulus retards subsequent acquisition of a conditioned response to that stimulus. The present study investigated the neuronal substrates of LI as assessed in a conditioned taste aversion paradigm by comparing regional c-Fos activation in pre- vs. non-pre-exposed animals. The LI paradigm involved a pre-exposure phase in which water-deprived rats were allowed access to either water (non-pre-exposed; NPE) or 5% sucrose (pre-exposed; PE), followed by a conditioning phase in which animals were allowed access to sucrose and subsequently injected with lithium chloride, and a test phase in which animals were allowed access to both sucrose and water. LI was assessed by comparing the %-sucrose consumed in PE and NPE groups on the test day. Two hours following the onset of the test phase, animals were perfused and their brains processed for c-Fos immunohistochemistry. PE animals drank significantly more sucrose on the test day, indicating the presence of LI. PE animals had significantly fewer FLI-positive cells in the striatum than NPE animals; however, no differences were seen in the nucleus accumbens. This difference in FLI was not due to a difference in sucrose consumption on the test day as there was no correlation between c-Fos and amount of sucrose consumed in the PE group. These data are consistent with previous data supporting a role for the striatum in the disruption of LI as assessed by CTA.

Behavioral processes mediating phencyclidine-induced decreases in voluntary sucrose consumption

Prior exposure to phencyclidine (PCP) has been shown to decrease voluntary sucrose consumption in rats, which may indicate reduced reward function. To further characterize the effects of PCP on sucrose consumption, we examined the dose-response relationship between PCP and sucrose consumption, the longevity of the effect, the effects of repeated injections of PCP, variation of the PCP effect across sucrose concentrations, and the effects of PCP on gustatory hedonic responses. A single injection of PCP (2.5-20 mg/kg) dose-dependently suppressed sucrose consumption 20 h post-injection, with significant decreases after 15 and 20 mg/kg PCP. These decreases were sustained three days following withdrawal from PCP. Repeated injections of PCP (7.5 mg/kg bid for 7 days) decreased sucrose consumption 20 h after withdrawal, which returned to baseline on the second day. A single injection of PCP (15 mg/kg) suppressed 0.15 M sucrose more than 1 M sucrose consumption, with no effect on 0.3 M sucrose, suggesting that PCP suppressed intake of moderately rewarding taste stimuli. Finally, a single injection of PCP (15 mg/kg) suppressed brief access (20 s) licking for the majority of concentrations of sucrose solutions offered (0.031 M, 0.062 M, 0.125 M, 0.25 M, 0.5 M, and 1.0 M), while it had no effect on licking for 0.016 M sucrose, water, or for bitter quinine hydrochloride solutions (range: 0.94 mM-30 mM), suggesting that the PCP effect is specific to palatable taste stimuli without disruption of sensitivity to taste quality or intensity. We conclude that PCP produces moderate anhedonia as reflected through a specific decrease in the sustained consumption of moderately palatable sucrose solutions.

The effects of phencyclidine (PCP) on anxiety-like behavior in the elevated plus maze and the light–dark exploration test are age dependent, sexually dimorphic, and task dependent

Previous research in our laboratory revealed sexually dimorphic effects of prior exposure to phencyclidine (PCP) on elevated plus maze behavior. In an attempt to examine the developmental time course of this effect and determine the extent to which it generalizes to other anxiety paradigms, young adult (61-64 days old) and adult (96-107 days old) male and female rats were treated with PCP (15 mg/kg) or saline. Following a two week withdrawal period, animals were tested in either the elevated plus maze (EPM) or a light-dark exploration (LD) test. In adults, both tests revealed a sexually dimorphic effect driven by PCP-induced decreases in anxiety in females as indicated by increased time spent in the open arms of the EPM and in the lit compartment of the LD test and increased anxiety in males as indicated by decreased time spent in the lit compartment of the LD. In young animals, PCP pretreatment decreased open arm exploration in the elevated plus maze, indicating increased anxiety. However, PCP increased time spent in the light compartment in the light-dark exploration test, indicating decreased anxiety. Corticosterone levels measured 15 min after the onset of the EPM failed to reveal an association between the behavioral effects of PCP and corticosterone levels. The results in adults substantiate the previously observed sexually dimorphic effect of PCP on elevated plus maze behavior in adults and indicate that the effect generalizes to another anxiety paradigm. The results in the younger animals suggest an age dependent effect of PCP on anxiety in general and indicate that behaviors in the elevated plus maze and the light-dark exploration test reflect dissociable psychobiological states.

Subchronic phencyclidine exposure potentiates the behavioral and c-Fos response to stressful stimuli in rats

Prior exposure to subchronic phencyclidine (PCP) produces behaviors argued to model schizophrenia in rats, including alterations in the behavioral responses to stress-inducing stimuli. Prior exposure to a single injection of PCP also produces a number of schizophrenia-like behaviors in rats, suggesting that a single injection of PCP is able to model schizophrenia-like behaviors as well. We examined the effects of prior exposure to either a single injection or subchronic PCP on stress-induced behavior and c-Fos-like immunoreactivity (FLI). Twenty-four hours after a single injection of PCP (15 mg/kg) or subchronic PCP (10 mg/kg for 14 days) or saline, male rats were exposed to either novel environment, forced swim, or left in their home cages. A single injection of PCP produced only small effects on stress-induced behavior and FLI: a drugxtime interaction on the number of cage crossings in the novel environment and a drugxcondition interaction on FLI in the shell of the nucleus accumbens. However, subchronic PCP decreased cage crosses and rears in the novel environment and increased immobility in the forced swim test. The increased immobility in the forced swim test was accompanied by increased striatal FLI. These data suggest that while a single injection of PCP produces only minimal alterations in the response to stressful stimuli, subchronic PCP produces a quantitatively greater effect. In addition, the observation that PCP pretreatment increased striatal FLI induced by forced swim but not novelty suggest that PCP alters the behavioral responses to these stressors via different neurochemical mechanisms.

The effects of phencyclidine pretreatment on amphetamine-induced behavior and c-Fos expression in the rat.

Previous data demonstrate that a single injection of phencyclidine enhances amphetamine-induced behaviors 24 h later, suggesting that the delayed effects of a single dose of phencyclidine may produce a schizophrenia-like state in animals. These behavioral changes were accompanied by altered patterns of c-Fos induction, suggesting possible neurochemical correlates to the observed behaviors. Because investigations into PCPs ability to model schizophrenia have found that the effects of repeated, or subchronic, PCP administration differ according to the dose and administration paradigm, this study sought to determine whether single and subchronic PCP exposure produce different effects on amphetamine-induced behaviors and c-Fos induction. No differences were observed between these administration paradigms; both single and subchronic PCP exposure enhanced amphetamine-induced c-Fos in the striatum, decreased c-Fos in the prefrontal cortex, and decreased the number of cage-crossings. However, the observation that PCP pretreatment affected c-Fos induction in the same manner observed previously while having an opposite effect on amphetamine-induced behavior suggests that these behavioral and neurochemical effects are dissociated.

Differential effects of acute and subchronic clozapine and haloperidol on phencyclidine-induced decreases in voluntary sucrose consumption in rats.

Prior exposure to the psychotomimetic drug phencyclidine (PCP) decreases voluntary sucrose consumption in rats. This may be indicative of reduced reward function, a phenomenon associated with negative schizophrenic symptomatology. Given that atypical antipsychotics have been shown to ameliorate negative symptoms of schizophrenia more effectively than typical neuroleptics, this effect should be reversed by clozapine but not haloperidol. PCP (15 mg/kg) or saline was administered 20 h prior to testing for voluntary sucrose consumption in non-deprived rats. In the acute experiments, rats were treated with clozapine (5 mg/kg), haloperidol (0.2 mg/kg), or vehicle 45 min prior to testing. In the subchronic experiments, rats were treated with clozapine (3 mg/kg, bid), haloperidol (0.5 mg/kg, bid), or vehicle for 10 days prior to PCP administration. Acute clozapine exacerbated the PCP-induced decrease in sucrose consumption without altering water consumption. Acute haloperidol produced an overall decrease in sucrose consumption in both PCP-pretreated and control groups. Subchronic treatment with clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption. The synergistic effect of acute clozapine and PCP may reflect a PCP-induced increase in the reward-reducing properties of CLZ, normally seen only at higher doses. The observation that subchronic clozapine, but not haloperidol, reversed PCP-induced decreases in sucrose consumption supports the hypothesis that this effect of PCP represents a plausible animal model for negative schizophrenic symptomatology.

Behavioral sensitization to amphetamine is not accompanied by a decrease in the number of c-Fos containing cells in the striatum.

The expression of c-Fos-like immunoreactivity (FLI) and chronic Fos-related antigen-like immunoreactivity (FRALI) accompanying behavioral sensitization to amphetamine was assessed in male rat striatum. Animals were treated for four days with amphetamine (A; 5 mg/kg) or vehicle (V) and challenged with A or V on the fifth day. The number of FLI-positive cells in the striatum was enhanced in V-A and A-A groups as compared to control (V-V), while the number of FRALI-positive cells in the striatum was enhanced in the A-V and A-A groups as compared to control. These results suggest that the absence of a decrease in the number of striatal FLI-positive cells accompanying chronic amphetamine treatment is not due to antibody cross-reactivity with chronic FRAs, and that behavioral sensitization to amphetamine is not accompanied by a change in the number of striatal cells expressing c-Fos.