5-HT modulation of auditory and visual sensorimotor gating: I. Effects of 5-HT releasers on sound and light prepulse inhibition in Wistar rats

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...

Section: Discussionmentioning

confidence: 99%

Diminished Acoustic Startle in Chronic Cocaine Users

Efferen

Duncan

Szilágyi

et al. 2000

“…Second, a major problem in studying the role of 5-HT in aversive learning and memory is that changes in 5-HT neurotransmission caused by the selective 5-HT 1A agonists (Rigdon and Weatherspoon 1992; Sipes and Geyer 1995) and the 5-HT releasing amphetamines (Davis and Sheard 1976;Geyer 1996;Kehne et al 1992;Kehne et al 1996) could alter sensorimotor reactivity at the time of training, which could subsequently influence the PA retention. In addition, 8-OH-DPAT and PCA also induce various behavioral effects; for example, modulate both general locomotor activity (Curzon 1990;Dourish et al 1985;Evenden and Angeby-Möller 1990;Hutson and Curzon 1989;, nociceptive thresholds (Hamon et al 1990;, and elicit a characteristic behavioral syndrome (5-HT syndrome) (Berendsen et al 1989;Jacobs 1976;Tricklebank et al 1984;Trulson and Jacobs 1976).…”

Section: Role Of Nonspecific Factors In Pamentioning

confidence: 99%

“…However, state-dependency does not explain the present results, because neither the selective 5-HT 1A agonists, including 8-OH-DPAT (Carli et al 1992;Misane et al 1998a), nor PCA (Ögren 1985bÖgren 1986a;Santucci et al 1996) when administered before both training and retention restored the retention performance to the control levels. In addition, in our previous studies, post-training administration of the 5-HT 1A agonists (Misane et al 1998a) or PCA (Ögren 1985b; Ögren 1986a) did not influence the 24-hour PA retention, showing that there is no long-term carry-over behavioral effect by the drug treatment.Second, a major problem in studying the role of 5-HT in aversive learning and memory is that changes in 5-HT neurotransmission caused by the selective 5-HT 1A agonists (Rigdon and Weatherspoon 1992; Sipes and Geyer 1995) and the 5-HT releasing amphetamines (Davis and Sheard 1976;Geyer 1996;Kehne et al 1992;Kehne et al 1996) could alter sensorimotor reactivity at the time of training, which could subsequently influence the PA retention. In addition, 8-OH-DPAT and PCA also induce various behavioral effects; for example, modulate both general locomotor activity (Curzon 1990;Dourish et al 1985;Evenden and Angeby-Möller 1990;Hutson and Curzon 1989;, nociceptive thresholds (Hamon et al 1990;, and elicit a characteristic behavioral syndrome (5-HT syndrome) (Berendsen et al 1989;Jacobs 1976;Tricklebank et al 1984;Trulson and Jacobs 1976).…”

mentioning

confidence: 99%

Multiple 5-HT Receptors in Passive Avoidance Comparative Studies of p-Chloroamphetamine and 8-OH-DPAT

Misane

2000

KEY WORDS : Passive avoidance; 5-HT receptors; 8-OH-DPAT; p-chloroamphetamine (PCA); m-chlorophenylpiperazine (mCPP); dopamineSerotonergic (5-HT) projections, arising from the midbrain raphe nuclei (Jacobs and Azmitia 1992; Vertes 1991) innervate limbic (amygdala and hippocampus) and cortical areas known to be involved in the cognition and processing of emotional events (Ambrogi Lorenzini et al. 1998;Gallagher and Chiba 1996;Heilman and Gilmore 1998;Lavond et al. 1993;Ledoux and Müller 1997;Pezzone et al. 1992).To investigate the role of the limbic and cortical 5-HT in behavior, different appproaches have been employed ranging from manipulations that result in multiple re- Received December 23, 1998; revised May 18, 1999; accepted July 13, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 2 Multiple 5-HT Receptors in Passive Avoidance 169 ceptor stimulation to the selective activation of 5-HT receptor subtypes. The former approach is of particular importance, because 5-HT neurotransmission seems to operate largely via non-or extrasynaptic mode of communication, also known as volume transmission (Agnati et al. 1995;Bunin and Wightman 1998;Descarries et al. 1990;Descarries et al. 1975;Dewar et al. 1991;Jansson et al. 1998). Thus, released 5-HT can act at a distance at multiple 5-HT receptors far away from the synaptic cleft, whereas selective 5-HT agonists act on all receptors of a specific subtype.Earlier studies have shown that treatments that increase 5-HT activity in the brain, such as 5-HT-releasing compounds [p-chloroamphetamine (PCA), MDMA, and MMAI] (Marona- Lewicka et al. 1996;McNamara et al. 1995;Ögren 1985b;Romano and Harvey 1994;Santucci et al. 1996) as well as the selective 5-HT reuptake inhibitors (SSRIs) (Altman et al. 1984;Lalonde and Vikis-Freibergs 1985;Lucki and Nobler 1985;McElroy et al. 1982;Meneses and Hong 1995;Ögren 1985b) can both enhance and impair performance in aversive learning tasks. Pretraining administration of PCA has been found to produce a marked impairment of both one-and two-way active avoidance acquisition and retention in the rat (Ögren 1982).Although PCA also causes an acute release of dopamine (DA) (Crespi et al. 1997;Henderson et al. 1993;Johnson et al. 1990;Ögren 1985b;Sharp et al. 1986) as well noradrenaline (NA) (Ögren 1982; Ögren 1985a) in the rat brain, its behavioral effects are mediated primarily via serotonergic mechanisms (Adell et al. 1989;Geyer 1996;Hutson and Curzon 1989;Trulson and Jacobs 1976). In support of this, the one-way active avoidance deficit by PCA was completely blocked when the rats were pretreated with 5-HT reuptake inhibitors zimeldine and fluoxetine but not by the NA uptake inhibitor desipramine (Ögren 1982). Zimeldine also blocked the 5-HT release induced by PCA (Ögren et al. 1982). Several nonselective 5-HT 2 antagonists, which, by themselves, did not impair avoidance learning, also produced a dose-dependent blockade of the PCAinduced deficit (Ögren 1986b). This finding suggested that the impairment of active avoidance acquisit...

“…For example, the PPI disruptive effects of the direct 5-HT2A receptor agonist DOI are prevented by the putative novel antipsychotic and 5-HT2A antagonist M100907 (Sipes and Geyer 1995b). Other 5-HT receptor agonists have also been shown to disrupt PPI, including 5-HT releasers (Mansbach et al 1989b;Kehne et al 1996; Martinez and Geyer 1997), direct 5-HT1A agonists such as 8-OH-DPAT (Rigdon and Weatherspoon 1992; Sipes and Geyer 1994, 1995a), and direct 5-HT1B agonists such as RU 24969 (Sipes and Geyer 1996;Dulawa et al 1997). Experimental paradigms have been used to elucidate features of the serotonergic regulation of PPI, ranging from the role of specific receptor subtypes in this process (Sipes and Geyer 1994), to their neuroanatomical localization (Sipes and Geyer 1995a;.…”

Section: Gating Of the Startle Reflex Can Be Assessed Via Measures Ofmentioning

confidence: 99%

Regulation of Sensorimotor Gating of the Startle Reflex by Serotonin 2A Receptors Ontogeny and Strain Differences

Farid

Martinez

Geyer

et al. 2000

gating of the startle reflex can be assessed via measures of prepulse inhibition (PPI), which is the reduction in startle magnitude when the startling stimulus is preceded immediately by a weak prepulse. PPI is reduced in humans with specific neuropsychiatric disorders and in rats after treatment with certain classes of drugs, including serotonin (5-HT) agonists. Because of the relative loss of PPI in inherited, neurodevelopmental disorders such as schizophrenia, there is great interest in understanding the inherited and developmental features of the neurochemical regulation of PPI in animals.In the present study, PPI was disrupted significantly by the 5-HT2A agonist 2, Prepulse inhibition (PPI) is the reduction in startle reflex magnitude when a startling stimulus is preceded by a weak prestimulus. PPI is diminished in patients with schizophrenia (Braff et al. 1978;Grillon et al. 1992;Bolino et al. 1994), obsessive compulsive disorder ), Huntington's disease (Swerdlow et al. 1995), nocturnal enuresis and attention deficit disorder (Ornitz et al. 1992), and Tourette Syndrome (Castellanos et al. 1996). These disorders are all marked by an inability to inhibit, or "gate" irrelevant information in sensory, motor, or cognitive domains. In schizophrenia, this loss of gating is conceptually linked to processes responsible for sensory flooding and cognitive fragmentation (McGhie and Chapman 1961).In the rat, disruption of PPI occurs after acute administration of dopamine (DA) agonists (Swerdlow et al. 1986;Mansbach et al. 1988), NMDA antagonists Geyer 1989a, 1991), or serotonin (5-HT) agonists (Mansbach et al. 1989b;Rigdon and Weatherspoon 1992;Kehne et al. 1992;Sipes and Geyer 1994). Studies in rats of the neural basis for drug effects on PPI may provide a means to further understand the pathophysiology of neuropsychiatric disorders characterized by deficits in 23 , NO . 6 sensorimotor gating (Swerdlow et al. 1994;. The present studies were designed to assess two aspects of the regulation of PPI by 5-HT2A receptors in rats: 1) the sensitivity to the PPI-disruptive effects of the 5-HT2A receptor agonist, 2,5-dimethoxy-4 iodopheny-lisopropylamine (DOI), in Wistar/Harlan ("WH") vs. Sprague Dawley/Harlan ("SDH") rats; and 2) the developmental time-course of the PPI-disruptive effects of DOI in male and female SDH pups.The regulation of PPI by brain 5-HT receptors is a topic of particular interest based on the 5-HT receptorblocking properties of novel atypical antipsychotics, such as clozapine, olanzapine, and quetiapine. In rats, PPI is disrupted by 5-HT agonists, and these effects are opposed by 5-HT antagonists. For example, the PPI disruptive effects of the direct 5-HT2A receptor agonist DOI are prevented by the putative novel antipsychotic and 5-HT2A antagonist M100907 (Sipes and Geyer 1995b). Other 5-HT receptor agonists have also been shown to disrupt PPI, including 5-HT releasers (Mansbach et al. 1989b;Kehne et al. 1996; Martinez and Geyer 1997), direct 5-HT1A agonists such as 8-OH-DPAT (Rigdon and Weathersp...