Diminished Acoustic Startle in Chronic Cocaine Users

Abstract

Chronic cocaine use has been shown to produce neurochemical alterations which persist after acute withdrawal. This study assessed the effects of cocaine use on the acoustic startle response and sensorimotor gating using prepulse inhibition (PPI) Chronic cocaine use causes physiological and neurochemical alterations which persist well after drug cessation. At the commencement of abstinence, adaptive decreases in dopamine (DA) receptor density (Kleven et al. 1990;Laurier et al. 1994) and DA uptake (Izenwasser and Cox 1990), as well as increases in DA transporter (DAT) mRNA expression (Pilotte et al. 1994;Wamsley and Alburges 1993) and cocaine binding sites (Malison et al. 1998), have been reported. As abstinence continues, there are decreases in basal DA efflux (Parsons et al. 1991;Weiss et al. 1992), DAT mRNA expression (Pilotte et al. 1994), DAT in nucleus accumbens (Wilson et al. 1994), and D 1 receptor density (Kleven et al. 1990), leading to an overall state of decreased dopaminergic neurotransmission (Kuhar and Pilotte 1996).The acoustic startle response under observation in this study is a well characterized response consisting of a reflexive contraction of the skeletal musculature in response to an intense, abrupt stimulus. It is mediated by a simple 3-synapse subcortical circuit Koch et al. 1993). In humans, the response is quantified using electromyographic (EMG) measurements of the obicularis oculi facial muscle (Hoffman and Searle 1968). This response is sensitive to dopaminergic modulation. Direct and indirect DA agonists, such as apomorphine, cocaine and d-amphetamine, increase startle amplitude in animals (Kehne and Sorenson 1978;Davis 1980;Johansson et al. 1995), whereas DA antagonists such as haloperidol and clozapine reduce startle amplitude (Mansbach et al. 1988;Johansson et al. 1995 The acoustic startle response can be attenuated if a weak, non-startling prestimulus (a prepulse) immediately precedes the startle stimulus (Graham 1975;Braff et al. 1992). This phenomenon is known as prepulse inhibition of startle (PPI), the pharmacology of which has been well characterized in animal studies. Dopamine agonists, both direct and indirect, reduce or eliminate PPI; D2 antagonists reverse the effect of agonists such as apomorphine (Mansbach et al. 1988). On the other hand, D1 antagonism fails to reverse the effect (Swerdlow et al. 1991).The aim of the present study was to examine the functional consequences of long-term cocaine use by studying the acoustic startle response and PPI of the acoustic startle response during abstinence following prolonged cocaine use. MATERIALS AND METHODS SubjectsSixty cocaine subjects and 20 normal individuals were screened in consideration for participation. Nine healthy male normal controls and 15 male cocaine users were enrolled in the study after signing a VA/NYU IRB approved consent form.All subjects were screened to rule out presence or history of psychiatric or medical pathology (excluding substance induced disorders for the cocaine users) using the Structured Cli...

Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine

“…LI has been linked primarily to activity within the nucleus accumbens and hippocampus, whereas the regulation of PPI is believed to occur in brain nuclei that extend from the prefrontal cortex to the pontine tegmentum (Weiner and Feldon 1997;Koch and Schnitzler 1997). Nevertheless, the attenuation of the startle response, which we report here during AMPH withdrawal, is similar to cocaine withdrawal effects on startle that have been reported previously in both humans and in rodents (Gordon and Rosen 1999;Efferen et al 2000;Adams et al 2001). Further investigations will be needed to clarify the neuronal mechanisms underlying this effect as well as the functional significance of this reduction in startle to an animal's emotional state.…”

“…In contrast, the acoustic startle response on day 4 was not significantly reduced in AMPH-pretreated animals, consistent with previous findings (Murphy et al 2001b), and after 2 months the effect was again absent, indicating that the startle reduction effect occurs within a restricted time window. Withdrawal from another psychostimulant drug, cocaine, also induces a reduction of the acoustic startle response in rats (Gordon and Rosen 1999;Adams et al 2001) and chronic cocaine users similarly exhibit marked impairments in the acoustic startle response (Efferen et al 2000).…”

Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys

“…The reflex is mediated by a simple three-synapse circuit (Davis et al 1982; Lang et al 2000; Lee et al 1996) and is sensitive to dopaminergic modulation by both direct and indirect dopamine agonists (Davis et al 1986b; Meloni and Davis 1999). Furthermore, chronic cocaine users have been shown to have diminished responses to startle stimuli presumably as a consequence of an extensive drug-taking history (Efferen et al 2000). It was, therefore, hypothesized that enduring neuroadaptive changes in the dopamine system due to chronic cocaine exposure would alter the responsiveness to acoustic startle.…”

“…This response is likewise sensitive to dopaminergic modulation by both direct and indirect dopamine agonists (Davis et al 1975, 1986b; Davis 1985; Meloni and Davis 1999). Moreover, chronic cocaine users in various phases of drug withdrawal have been shown to have diminished responses to startle stimuli (Efferen et al 2000) as do rats given daily cocaine for 8 weeks (Adams et al 2001). This may be the result of persistent changes to the dopamine system as a consequence of an extensive drug-taking history.…”

Relationship between Toxoplasma gondii seropositivity and acoustic startle response in an inner-city population

“…For each of the following diagnoses they were coded for the current or previous presence of a diagnosis of: schizophrenia (SCZ), major depression (MDD), posttraumatic stress disorder (PTSD), and any substance use disorder (including alcohol or any drug of abuse). Because of our prior published findings of low startle magnitude in cocaine addicted subjects (Efferen et al 2000; Corcoran et al 2011) we also created a specific dichotomous variable to define whether or not subjects had current or past history of cocaine use disorder. Finally, a composite dichotomous variable was created to define whether subjects had current or past history of any primary psychotic diagnosis on the SCID or MINI interview (including DSM-IV schizophrenia, schizoaffective disorder, schizotypal disorder, delusional disorder, brief psychotic disorder, unspecified psychosis).…”