Proximal ethanol pretreatment interferes with acquisition of ethanol-induced conditioned place preference

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, United States
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 12/2006; 85(3):612-9. DOI: 10.1016/j.pbb.2006.10.016
Source: PubMed


Neurobiological mechanisms underlying rewarding and aversive effects of drugs are often studied by examining effects of various pretreatments on acquisition of conditioned place preference (CPP) or conditioned place aversion (CPA). However, few studies have looked at effects of pretreatment with the same drug used during conditioning. Such studies might offer insight into agonist actions on conditioning while also mimicking real world contingencies experienced by drug users. Previous work from our laboratory, which showed that same drug pre-exposure interfered with acquisition of ethanol CPA but not CPP, was limited by the use of only one pre-treatment time interval (65 min). Thus, the present studies were designed to study other intervals (-5, -15, -30). Pretreatment of DBA/2J mice with ethanol (2 g/kg) reduced the activity response normally evoked by the conditioning dose (2 g/kg) at all pretreatment times, but acquisition of CPP was disrupted only by pretreatment at -5 min. The overall pattern of findings suggests that ethanol's early pharmacological effects interfered with learning the association between the conditioned stimulus (CS) and ethanol 5 min later. Thus, one would expect ethanol agonists, when administered in close proximity to CS-ethanol pairings, to interfere with control of ethanol seeking by that CS.

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    • "NMDAR activation in the VTA is required for the learning of drug-associated cues assessed with a CPP paradigm (Harris et al., 2004; Zweifel et al., 2008). In accordance with this idea, acute ethanol exposure, which inhibits NMDARs (Lovinger et al., 1989), has been shown to interfere with CPP when administered immediately before conditioning sessions (Cunningham and Gremel, 2006). In contrast, our CPP experiments show that the same repeated ethanol treatment that enhances NMDAR LTP also enhances subsequent learning of cocaine-associated cues. "
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    ABSTRACT: Alcohol addiction (alcoholism) is one of the most prevalent substance abuse disorders worldwide. Addiction is thought to arise, in part, from a maladaptive learning process in which enduring memories of drug experiences are formed. However, alcohol (ethanol) generally interferes with synaptic plasticity mechanisms in the CNS and thus impairs various types of learning and memory. Therefore, it is unclear how powerful memories associated with alcohol experience are formed during the development of alcoholism. Here, using brain slice electrophysiology in mice, we show that repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 d) causes increased susceptibility to the induction of long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated transmission in mesolimbic dopamine neurons, a form of synaptic plasticity that may drive the learning of stimuli associated with rewards, including drugs of abuse. Enhancement of NMDAR plasticity results from an increase in the potency of inositol 1,4,5-trisphosphate (IP(3)) in producing facilitation of action potential-evoked Ca(2+) signals, which is critical for LTP induction. This increase in IP(3) effect, which lasts for a week but not a month after ethanol withdrawal, occurs through a protein kinase A (PKA)-dependent mechanism. Corticotropin-releasing factor, a stress-related neuropeptide implicated in alcoholism and other addictions, further amplifies the PKA-mediated increase in IP(3) effect in ethanol-treated mice. Finally, we found that ethanol-treated mice display enhanced place conditioning induced by the psychostimulant cocaine. These data suggest that repeated ethanol experience may promote the formation of drug-associated memories by enhancing synaptic plasticity of NMDARs in dopamine neurons.
    Full-text · Article · Apr 2011 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "Pretreatment injections were given in the home cage 30 min before conditioning trials in Experiments 2 (vehicle or SB-334867) and 5 (vehicle only). This conditioning procedure has been repeatedly shown to induce a strong ethanol CPP in DBA/2J mice in our laboratory (Cunningham et al. 2006). "
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    ABSTRACT: Recent studies suggest that orexin/hypocretin is involved in drug reward and drug-seeking behaviors, including ethanol self-administration. However, orexin's role in ethanol-induced seeking behaviors remains unclear. These studies examined the role of orexin in the acquisition and expression of ethanol conditioned place preference (CPP) using the orexin 1 receptor (OX1R) antagonist SB-334867. Effects of SB-334867 (0-30 mg/kg) on locomotor activity were determined in DBA/2J mice (Experiment 1). SB-334867 (0-30 mg/kg) was administered during acquisition of ethanol (2 g/kg) CPP to determine whether orexin signaling is required (Experiment 2). Blood ethanol concentrations (BECs) were measured after ethanol (2 g/kg) injection to determine whether SB-334867 (30 mg/kg) pretreatment altered ethanol pharmacokinetics (Experiment 3). Finally, SB-334867 (0-40 mg/kg) was given before ethanol-free preference testing (Experiments 4 and 5). SB-334867 did not alter basal locomotor activity (Experiment 1). SB-334867 (30 mg/kg) reduced ethanol-induced locomotor stimulation, but did not affect the acquisition of ethanol CPP (Experiment 2) or BEC, suggesting no alteration in ethanol pharmacokinetics (Experiment 3). Although OX1R antagonism blocked expression of a weak ethanol CPP (Experiment 4), it did not affect expression of a moderate to strong CPP (Experiment 5). Blockade of OX1R by systemic administration of SB-334867 reduced ethanol-stimulated activity, but did not affect acquisition or expression of ethanol-induced CPP, suggesting that orexin does not influence ethanol's primary or conditioned rewarding effects. Other neurotransmitter systems may be sufficient to support acquisition and expression of CPP despite alterations in orexin signaling.
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    • "El etanol provoca tanto efectos aversivos como apetitivos y neutros y eso se refleja también en los experimentos de CL. Las condiciones bajo las cuales los animales desarrollan PLC o ALC dependen de muchos factores, tales como la vía de administración (intaperitoneal -i.p.-, intragástrica, consumo forzado, intravenoso, etc.), cepa o línea de rata empleada, experiencia previa con la droga previa al condicionamiento (Busse, Lawrence y Riley, 2005; Cunningham y Gremel, 2006), el tipo de aparato y de procedimiento usado (Fidler, Bakner y Cunningham, 2004), y la temperatura a la cual están expuestos los animales, ya que diversos estudios sugieren que los efectos térmicos del etanol podrían ser importantes en la modulación de sus efectos motivacionales. Por ejemplo, Dickinson y Cunningham (1998), hallaron que exponiendo a ratones a diversas temperaturas durante la fase de condicionamiento (frío 10°C, normal 21°C y cálido 34°C) y luego probando el CL en la misma o en diferente temperatura del condicionamiento, solamente desarrollaron PLC los animales condicionados y probados en un contexto con temperatura normal. "
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    ABSTRACT: One of the most common procedures used to assess the hedonic value of a drug is the conditioned place (CP) which explores the preference or the aversion towards a previously drug paired context. In this paper we report on the different apparatus, procedures and dependant measures used on CP and the main results found using ethanol. Finally we present a CP between-within subjects experiment on rats. The experiment consisted in three phases: (1) Pre-Test, we measured the animal¿s preference towards both contexts black place (BP) and white place (WP); (2) Conditioning, each animal received ethanol (dose: 0.5g/kg, i.p.) paired with the non preferred context and saline paired with the preferred context on alternate trials. A control group received vehicle in both contexts; (3) Post-Test same as pre-test. In both tests the time spent in each context was measured. The ethanol treated group reversed its place preference, whereas the saline group kept its initial preference. From this study we inferred that under this dose, ethanol has a positive hedonic value.
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