Effects of psychostimulant withdrawal on latent inhibition of conditioned active avoidance and prepulse inhibition of the acoustic startle response

Abstract

Rationale: Chronic intermittent administration of amphetamine and cocaine can precipitate psychotic episodes in humans and produce persistent behavioral changes (i.e. increased locomotion, stereotypy) in the rat. The psychostimulant sensitization model of psychosis holds that the repeated administration of drugs such as amphetamine and cocaine induces long-lasting neuroadaptations and behavioral outcomes in animals that parallel aspects of the schizophrenic condition. Objectives: In the present study, we attempted to validate this model further by examining the effects of short-term withdrawal from repeated administration of cocaine and amphetamine on performance in two animal behavioral models of cognitive deficits found in schizophrenia: latent inhibition and prepulse inhibition. Reductions in both of these behavioral phenomena have been reported in schizophrenic patients and in acutely amphetamine-treated rats. Methods: Animals were tested after 4 days of withdrawal from 5 days of daily systemic 20 mg/kg cocaine or 1.5 mg/kg amphetamine injections for either latent inhibition of two-way active avoidance acquisition or prepulse inhibition of an acoustic startle response. Results: Our results indicate that, rather than reducing the expression of these behaviors, withdrawal from either cocaine or amphetamine enhanced the expression of latent inhibition of the active avoidance response while having no effect on prepulse inhibition of acoustic startle. Conclusions: These data indicate that although the sensitized response to amphetamine and cocaine administration may model some aspects of schizophrenic psychosis, behaviors exhibited by sensitized animals in the absence of an acute drug challenge are not consistent with models of the positive symptoms of schizophrenia.

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine

“…Manipulations of the PPI testing environment that were intended to simulate the experimental conditions considered optimal for demonstrating behavioral sensitization (contextual associations, presence of a DA agonist challenge, later withdrawal time points for testing) likewise did not reveal any increased sensitivity of AMPH-withdrawn animals to PPI disruption. Such a dissociation between LI and PPI has been shown previously following other behavioral and pharmacological treatments (Wilkinson et al 1994;Feldon et al 2000;Murphy et al 2001a). The existence of this dissociation may be due at least in part to the suggested involvement of different brain regions in the mediation of LI and PPI.…”

Sensitization to amphetamine, but not phencyclidine, disrupts prepulse inhibition and latent inhibition

“…For example, although Druhan et al (1998) found a leftward shift in the Amp dose-response curve, there appeared to be little evidence of sensitization to a challenge dose of 0.5 mg/kg. Similarly, although the rats used by Murphy et al (2001a) showed enhanced responses to an Amp challenge of 1.5 mg/kg these effects were reported as being not statistically significant. These small effects are in contrast with the robust (250%) increase in Amp-stimulated activity observed with our rats.…”

“…A striking feature of these studies is the variety in methods used to induce sensitization particularly regarding the dose of Amp and the frequency of injections. Two of these studies used 1.5 mg/kg on five consecutive days (Murphy et al 2001a) and 2 mg/kg every 3 days for six injections (Druhan et al 1998). The strength of sensitization, as indexed by shifts in the magnitude of locomotor stimulant effects of a challenge dose of Amp, seem to differ across these various schedules.…”

“…Some previous reports indicated that Amp-sensitized rats show reduced LI when tested drug free (Murphy et al 2001b;Russig et al 2002). However, this group has also reported enhanced LI resulting from Amp sensitization (Murphy et al 2001a). The reasons for these opposite effects of Amp sensitization on LI are not clear but may relate to differences in the dosing regimen of Amp between the various studies.…”

Sensitization to amphetamine, but not PCP, impairs attentional set shifting: reversal by a D1 receptor agonist injected into the medial prefrontal cortex

“…Recent reports also describe information processing deficits following sensitizing regimens of amphetamine. Rats with prior exposure to amphetamine show reduced prepulse inhibition (PPI) of the acoustic startle reflex (Tenn et al 2003) and disrupted latent inhibition (LI) (Murphy et al 2001), and exhibit a variety of deficits in tests of visual attention (Dalley et al 2005;Deller and Sarter 1998;Kondrad and Burk 2004). Thus, exposure to stimulants may also alter cognitive function.…”