Increased Alcohol Self-administration Research Articles

Early social isolation differentially affects the glucocorticoid receptor system and alcohol-seeking behavior in male and female Marchigian Sardinian alcohol-preferring rats

Adverse early life experiences during postnatal development can evoke long-lasting neurobiological changes in stress systems, thereby affecting subsequent behaviors including propensity to develop alcohol use disorder. Here, we exposed genetically selected male and female Marchigian Sardinian alcohol-preferring (msP) and Wistar rats to mild, repeated social deprivation from postnatal day 14 (PND14) to PND21 and investigated the effect of the early social isolation (ESI) on the glucocorticoid receptor (GR) system and on the propensity to drink and seek alcohol in adulthood. We found that ESI resulted in higher levels of GR gene and protein expression in the prefrontal cortex (PFC) in male but not female msP rats. In female Wistars, ESI resulted in significant downregulation of Nr3c1 mRNA levels and lower GR protein levels. In male and female msP rats, plasma corticosterone levels on PND35 were similar and unaffected by ESI. Wistar females exhibited higher levels of corticosterone compared with males, independently from ESI. In alcohol self-administration experiments we found that the pharmacological stressor yohimbine (0.0, 0.312, 0.625, and 1.25 mg/kg) increased alcohol self-administration in both rat lines, regardless of ESI. After extinction, 0.625 mg/kg yohimbine significantly reinstated alcohol seeking in female rats only. ESI enhanced reinstatement in female msP rats. Overall, the present results indicate that repeated social deprivation during the third week of postnatal life affects GR expression in a strain- and sex-dependent manner: such effect may contribute, at least partially, to the heightened sensitivity of female msP rats to the effects of yohimbine-induced alcohol seeking.

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system's involvement in the development and maintenance of alcohol use disorder (AUD). In the present study we administered the TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption on a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg. However, when 1.0 mg/kg was given on consecutive days, alcohol intake increased in the days following injections specifically in females. In a second experiment, we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the poly(I:C) dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions in alcohol intake on injection days in females that were not accompanied by subsequent increases. The poly(I:C) dose was increased to 9.0 mg/kg for one final pair of injections which led to reductions in intake in both males and females followed by a male specific delayed increase in alcohol intake. Overall, repeated poly(I:C) administration was able to increase subsequent alcohol consumption in both sexes, with females showing an increase at a lower dose than males. These findings support TLR3 agonism in contributing to increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.

The serotonin 2A receptor agonist TCB-2 attenuates heavy alcohol drinking and alcohol-induced midbrain inhibitory plasticity.

Disruption of neuronal chloride ion (Cl- ) homeostasis has been linked to several pathological conditions, including substance use disorder, yet targeted pharmacotherapies are lacking. In this study, we explored the potential of serotonin 2A receptor (5-HT2A R) agonism to reduce alcohol consumption in male wild-type C57Bl/6J mice and to ameliorate alcohol-induced inhibitory plasticity in the midbrain. We found that administration of the putative 5-HT2A R agonist TCB-2 attenuated alcohol consumption and preference but did not alter water or saccharin consumption. We hypothesized that the selective behavioural effects of TCB-2 on alcohol drinking were due, at least in part, to effects of the agonist on ventral tegmental area (VTA) neurocircuitry. Alcohol consumption impairs Cl- transport in VTA GABA neurons, which acts as a molecular adaptation leading to increased alcohol self-administration. Using ex vivo electrophysiological recordings, we found that exposure to either intermittent volitional alcohol drinking or an acute alcohol injection diminished homeostatic Cl- transport in VTA GABA neurons. Critically, in vivo TCB-2 administration normalized Cl- transport in the VTA after alcohol exposure. Thus, we show a potent effect of alcohol consumption on VTA inhibitory circuitry, in the form of dysregulated Cl- homeostasis that is reversible with agonism of 5-HT2A Rs. Our results provide insight into the potential therapeutic action of 5-HT2A R agonists for alcohol abuse.

Caffeine increases alcohol self-administration, an effect that is independent of dopamine D2 receptor function.

The rising popularity of alcohol mixed with energy drinks (AmEDs) has become a significant public health concern, with AmED users reporting higher levels of alcohol intake than non-AmED users. One mechanism proposed to explain this heightened level of alcohol intake in AmED users is that the high levels of caffeine found in energy drinks may increase the positive reinforcing properties of alcohol, an effect that may be dependent on interactions between adenosine receptor signaling pathways and the dopamine D2 receptor. Therefore, the purpose of the current study was to confirm whether caffeine does increase the positive reinforcing effects of alcohol using both fixed ratio (FR) and progressive ratio (PR) designs, and to investigate a potential role of the dopamine D2 receptor to caffeine-induced increases in alcohol self-administration. Male Long-Evans rats were trained to self-administer a sweetened alcohol solution (10% v/v alcohol+2% w/v sucrose) on an FR2 schedule of reinforcement, and the effects of caffeine (0, 5, 10, and 20mg/kg, i. p. [intraperitoneally]) on the maintenance of alcohol self-administration and alcohol break point were examined. Parallel experiments in rats trained to self-administer sucrose (0.8% w/v) were conducted to determine whether caffeine's reinforcement-enhancing effects extended to a non-drug reinforcer. Caffeine pretreatment (5-10mg/kg) significantly increased sweetened alcohol self-administration and motivation for a sweetened alcohol reinforcer. However, similar increases in self-administration of a non-drug reinforcer were not observed. Contrary to our hypothesis, the D2 receptor antagonist eticlopride did not block a caffeine-induced increase in sweetened alcohol self-administration, nor did it alter caffeine-induced increases in motivation for a sweetened alcohol reinforcer. Taken together, these results support the hypothesis that caffeine increases the positive reinforcing effects of alcohol, which may explain caffeine-induced increases in alcohol intake. However, the reinforcement-enhancing effects of caffeine appear to be independent of D2 receptor function.

Increased alcohol self-administration following exposure to the predator odor TMT in active coping female rats

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly comorbid. Additionally, individual differences in response to stress suggest resilient and susceptible populations. The current study exposed male and female Long Evans rats to the synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to examine individual differences in stress-reactive behaviors (digging and immobility) and whether these differences were related to subsequent alcohol drinking. Male and female Long Evans rats were trained on operant alcohol self-administration. After 9 sessions, rats underwent exposure to TMT or water (Control) in a distinct context. 6 days after TMT exposure, rats underwent re-exposure to the TMT-paired context (without TMT), and a series of behavioral assessments (acoustic startle, zero maze, light/dark box), after which rats resumed alcohol self-administration. TMT subgroups were created using a ratio of digging to immobility behavior during TMT exposure and rats with a ratio score < 1.0 or> 1.0 were grouped into TMT-1 (low digging/high immobility) or TMT-2 (high digging/low immobility), respectively. All male rats exposed to TMT met criteria for TMT-1, while female rats were divided into the two subgroups. In females, high digging/low immobility behavior during TMT exposure (TMT-2) was related to increased alcohol self-administration, but this was not observed in males or females that engaged in low digging/high immobility (TMT-1). These data show that individual differences in stress-reactivity can lead to lasting behavioral changes which may lead to a better understanding of increases in alcohol drinking following stress in females.

Chronic nicotine increases alcohol self-administration in adult male Wistar rats.

Alcohol and nicotine co-dependence is common in humans, and nicotine increases alcohol drinking in humans without alcohol use disorder (AUD). Nevertheless, there is little basic research on the interactions between the reinforcing effects of these two drugs. The aim of this study was to investigate the effects of chronic nicotine injections on oral alcohol self-administration in alcohol non-dependent rats. After stable alcohol self-administration was reached (baseline) and a period without alcohol access, adult male rats were treated with chronic nicotine or saline injections for 105days during which time they were tested intermittently for alcohol self-administration. There were 3 experimental groups: (1) saline, rats treated with saline for 105days; (2) early nicotine, rats treated with nicotine for 70days, and then with saline for 35days; and (3) late nicotine: rats treated with saline for 35days, and then with nicotine for 70days. Our results indicate that (1) chronic nicotine increases alcohol consumption regardless of whether exposure to alcohol was interrupted (early nicotine) or not (late nicotine) before the start of nicotine treatment, (2) the number of alcohol reinforcements correlates to blood-alcohol levels, and (3) alcohol self-administration rapidly decreases when nicotine is no longer available (early nicotine). These discoveries may have clinical implications in social drinkers that use nicotine products, in that chronic nicotine can escalate alcohol drinking and cessation of nicotine exposure may decrease alcohol use.

The synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline increases alcohol self-administration and alters basolateral amygdala response to alcohol in rats.

Post-traumatic stress disorder (PTSD) is a psychiatric illness that can increase the risk for developing an alcohol use disorder (AUD). While clinical data has been useful in identifying similarities in the neurobiological bases of these disorders, preclinical models are essential for understanding the mechanism(s) by which stressors increase the risk for escalated alcohol consumption. The purpose of these studies was to examine if exposure of male Long-Evans rats to the synthetically derived predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT; a component of fox feces) would increase sweetened alcohol self-administration, potentially by facilitating transfer of salience towards cues, and alter neuronal response to alcohol as measured by the immediate early gene c-Fos. In experiment 1, rats exposed to repeated (4×) TMT showed reductions in port entries in Pavlovian conditioned approach and increases in sweetened alcohol self-administration. In experiment 2, rats exposed to repeated TMT showed blunted basolateral amygdala c-Fos response to alcohol. In experiment 3, rats exposed to single, but not repeated TMT, showed increases in sweetened alcohol self-administration, and no change in anxiety-like behavior or hyperarousal. In experiment 4, rats continued to show a significant corticosterone response to TMT after repeated exposures. In summary, exposure of male rats to TMT can cause escalations in sweetened alcohol self-administration and reduction in BLA response to alcohol. These studies outline and utilize a novel preclinical model that can be used to further neurobiological understanding of the emergence of escalated alcohol consumption following stress exposure.

5-HT2A receptor activation normalizes stress-induced dysregulation of GABAergic signaling in the ventral tegmental area

Stress is known to alter GABAergic signaling in the ventral tegmental area (VTA), and this inhibitory plasticity is associated with increased alcohol self-administration. In humans, serotonin 2A receptor (5-HT2AR) agonists can treat stress- and alcohol-related disorders, but the neural substrates are ill-defined. Thus, we reasoned that 5-HT2AR pharmacotherapies may ameliorate the stress-induced dysregulated inhibitory VTA circuitry that contributes to subsequent alcohol abuse. We found that acute stress exposure in mice compromised GABA-mediated inhibition of VTA GABA neurons corresponding with increased ethanol-induced GABAergic transmission. This stress-induced inhibitory plasticity was reversible by applying the 5-HT2AR agonist TCB-2 ex vivo via functional enhancement of the potassium-chloride cotransporter KCC2. The signaling pathway linking 5-HT2AR activation and normalization of KCC2 function was dependent on protein kinase C signaling and phosphorylation of KCC2 at serine 940 (S940), as mutation of S940 to alanine prevented restoration of chloride transport function by TCB-2. Through positive modulation of KCC2, TCB-2 also reduced elevated ethanol-induced GABAergic signaling after stress exposure that has previously been linked to increased ethanol consumption. Collectively, these findings provide mechanistic insights into the therapeutic action of 5-HT2AR agonists at the neuronal and circuit levels of brain reward circuitry.

Functional role for cortical-striatal circuitry in modulating alcohol self-administration

The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4Di-Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC→AcbC or IC→AcbC projections, to investigate the role of cortical-striatal circuitry in modulating alcohol self-administration. Chemogenetically silencing the mPFC decreased alcohol self-administration, while silencing the IC increased alcohol self-administration, an effect absent in mCherry-Controls. Interestingly, silencing mPFC→AcbC projections had no effect on alcohol self-administration. In contrast, silencing IC→AcbC projections decreased alcohol self-administration, in a reinforcer-specific manner as there was no effect in rats trained to self-administer sucrose (0.8%, w/v). Additionally, no change in self-administration was observed in the mCherry-Controls. Together these data demonstrate the complex role of the cortical-striatal circuitry while implicating a role for the insula-striatal circuit in modulating ongoing alcohol self-administration.

Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals.

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut-brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg-1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen's d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.

Re-exposure to nicotine-associated context from adolescence enhances alcohol intake in adulthood

Alcohol and nicotine are the two most commonly-abused substances and are often used together. Nicotine enhances alcohol-drinking behaviors in humans and in animals, and was suggested to enhance the reinforcing properties of other reinforcers. Here, we show that nicotine-associated environment, rather than nicotine itself, enhances alcohol intake in rats. Adolescent rats received repeated intermittent injections of nicotine (0.4 mg/kg, i.p., 5 injections, every 3rd day) or saline. The injection was paired with their home cage, or with the subsequent alcohol self-administration context. Rats were then trained to self-administer 20% alcohol. Nicotine given in the home cage did not alter subsequent alcohol intake. However, pairing nicotine with the operant chamber during adolescence led to a long-lasting increased alcohol self-administration in adulthood, compared to nicotine pre-treatment in other contexts. This effect persisted 3 months after nicotine cessation, in a relapse test after abstinence. Furthermore, re-exposure to the nicotine-associated context in adult rats led to a decrease in glial cell line-derived neurotrophic factor (Gdnf) mRNA expression in the ventral tegmental area, an effect that leads to increased alcohol consumption, as we have previously reported. Our findings suggest that retrieval of nicotine-associated contextual memories from adolescence may gate alcohol intake in adulthood, with a possible involvement of GDNF.

Exposure to Nicotine in Adult, but not Adolescent, Rats Increases Alcohol Self-Administration in Adulthood

Among drugs of abuse, nicotine and alcohol are the most consumed in the world, and are often co-abused. Evidence has shown that nicotine enhances the consumption and subjective effects of ethanol. How nicotine increases alcohol consumption is an interesting question that is still left unanswered. We assessed whether repeated treatment with nicotine during adolescence or adulthood could increase operant alcohol selfadministration. Male adolescent and adult rats (postnatal day [PND] 28 and 60, respectively) were injected with nicotine (1.0 mg/kg, subcutaneously [s.c.], three times a day for 10 days). During this period, the control group received saline injections (0.1 ml/kg; s.c). On PND 72, adolescent and adult rats pretreated with nicotine were subjected to ethanol self-administration procedures. Alcohol oral self-administration patterns were evaluated using a progressive ratio schedule of reinforcement and 24-hour unlimited access to ethanol. Our results showed that nicotine pretreatment in adult rats increases the motivation for alcohol consumption. However, nicotine exposure during adolescence does not affect alcohol-consuming behaviors in adulthood.

Stress Increases Ethanol Self-Administration via a Shift toward Excitatory GABA Signaling in the Ventral Tegmental Area

Stress is a well-known risk factor for subsequent alcohol abuse, but the neural mechanisms underlying interactions between stress and alcohol remain largely unknown. Addictive drug reinforcement and stress signaling involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to stress attenuates alcohol-induced dopamine responses and increases alcohol self-administration. The blunted dopamine signaling resulted from ethanol-induced excitation of GABA neurons in the ventral tegmental area. Excitation of GABA neurons was mediated by GABAA receptor activation and involved stress-induced functional downregulation of the K+, Cl- cotransporter, KCC2. Blocking stress hormone receptors, enhancing KCC2 function, or preventing excitatory GABA signaling by alternative methods all prevented the attenuated alcohol-induced dopamine response and prevented the increased alcohol self-administration. These results demonstrate that stress alters the neural and behavioral responses to alcohol through a neuroendocrine signal that shifts inhibitory GABA transmission toward excitation.

Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2

Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.

Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats

Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats

Antagonism of RXFP-3 receptor in the lateral hypothalamus increases alcohol self-administration in rats

Event Abstract Back to Event Antagonism of RXFP-3 receptor in the lateral hypothalamus increases alcohol self-administration in rats Christina J. Perry1, 2*, Hanna E. Kastman1, 2, Sarah S. Ch'Ng1, 2, Leigh C. Walker1, 2, Craig M. Smith1, 2, Andrew L. Gundlach1, 2 and Andrew J. Lawrence1, 2 1 The Florey Institute of Neuroscience and Mental Health, Behavioural Neuroscience, Australia 2 The University of Melbourne, Florey Department of Neuroscience and Mental Health, Australia Alcohol is the most widely abused drug worldwide, and alcohol abuse is a significant contributor to the global burden of disease. The search for novel and effective therapeutic targets to treat alcoholism is an ongoing task, especially given the high rates of relapse observed following alcohol rehabilitation. RXFP-3, the cognate receptor for the neuropeptide relaxin-3, is a potential therapeutic target. Recently we showed that RXFP3 is necessary for alcohol consumption and seeking, since central antagonism of this receptor reduced alcohol self-administration and relapse-like behaviour in alcohol preferring rats. Relaxin-3 is predominantly expressed in the brainstem, in neurons that project rostrally to the septum, hippocampus and lateral hypothalamus (LH). Of these, the lateral hypothalamus in particular is frequently implicated in alcohol consumption and relapse to alcohol-seeking. We sought, therefore, to examine the effect of RXFP3 antagonism in the LH. Alcohol-preferring P rats were trained to lever press for 10% ethanol for a minimum of 30 days. The selective antagonist R3(B1-22)R was then infused bilaterally into the LH prior to a standard self-administration session. In contrast to the effect of a central (icv) or intra-BNST infusion, rats showed increased alcohol consumption following administration of R3(B1-22)R compared to vehicle. To better understand this unexpected result we subsequently sought to characterise RXFP-3 positive neurons in the hypothalamus using a transgenic reporter mouse expressing GFP protein on RXFP-3 neurons. RXFP-3 receptors were expressed on orexin negative neurons that project to the ventral tegmental area (VTA). These findings have implications for understanding how relaxin 3 acts centrally to regulate alcohol-seeking and alcohol consumption, and on-going studies will elucidate the mechanism behind this finding, which somewhat parallels observations with the opioid receptor antagonist naltrexone. Keywords: Hypothalamus, Neuron, RXFP3, Alcohol consumption, alcohol seeking behaviour Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: YIC01: Young Investigator Colloquium 1 Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Perry CJ, Kastman HE, Ch'Ng SS, Walker LC, Smith CM, Gundlach AL and Lawrence AJ (2016). Antagonism of RXFP-3 receptor in the lateral hypothalamus increases alcohol self-administration in rats. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00053 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Christina J Perry, The Florey Institute of Neuroscience and Mental Health, Behavioural Neuroscience, Melbourne, Victoria, Australia, christina.perry@mq.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Christina J Perry Hanna E Kastman Sarah S Ch'Ng Leigh C Walker Craig M Smith Andrew L Gundlach Andrew J Lawrence Google Christina J Perry Hanna E Kastman Sarah S Ch'Ng Leigh C Walker Craig M Smith Andrew L Gundlach Andrew J Lawrence Google Scholar Christina J Perry Hanna E Kastman Sarah S Ch'Ng Leigh C Walker Craig M Smith Andrew L Gundlach Andrew J Lawrence PubMed Christina J Perry Hanna E Kastman Sarah S Ch'Ng Leigh C Walker Craig M Smith Andrew L Gundlach Andrew J Lawrence Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats

Gabapentin, a drug used in the treatment of epileptic seizures and neuropathic pain, has shown efficacy in the treatment of alcohol dependence. Moreover, given that gabapentin is used in the general population (e.g., non-dependent individuals, social drinkers), we sought to utilize preclinical assessments to examine the effects of gabapentin on sensitivity to moderate alcohol doses and alcohol self-administration in rats with a history of moderate drinking. To this end, we assessed whether gabapentin (0, 10, 30, 120 mg/kg, IG) pretreatment alters sensitivity to experimenter- and self-administered alcohol, and whether gabapentin alone has alcohol-like discriminative stimulus effects in rats trained to discriminate alcohol dose (1 g/kg, IG) vs. water. Second, we assessed whether gabapentin (0, 10, 30, 60 mg/kg, IG) would alter alcohol self-administration. Gabapentin pretreatment potentiated the interoceptive effects of both experimenter-administered and self-administered alcohol in discrimination-trained rats. Additionally, the highest gabapentin doses tested (30 and 120 mg/kg) were found to have partial alcohol-like discriminative stimulus effects when administered alone (e.g., without alcohol). In the self-administration trained rats, gabapentin pretreatment (60 mg/kg) resulted in an escalation in alcohol self-administration. Given the importance of interoceptive drug cues in priming and maintaining self-administration, these data define a specific behavioral mechanism (i.e., potentiation of alcohol effects) by which gabapentin may increase alcohol self-administration in non-dependent populations.

SY33-1 * CIGARETTES AND ALCOHOL: HOW NICOTINE PROMOTES DRINKING VIA STRESS HORMONES

Although tobacco smoking is a well-known risk factor for alcohol abuse, the neural events contributing to this risk remain largely unknown. Nicotine and alcohol share many common cellular and molecular targets that converge upon the mesolimbic dopamine system. Our studies demonstrate that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The decreased dopamine response arises from increased inhibitory synaptic transmission onto midbrain dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevents all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence reward-related responses to alcohol.

Operant self-administration of alcohol and nicotine in a preclinical model of co-abuse

Alcohol and nicotine are often taken together. In humans, intake of nicotine, via smoked tobacco, increases alcohol drinking, and alcohol increases smoking. Chronic nicotine treatment increases alcohol self-administration (SA) in laboratory animals; the reverse relationship is less clear. Most animal work modeling this has used passive administration, which lacks relevance to human co-abuse. Here, we describe a model based on sequential operant SA of alcohol and nicotine. Animals are first trained on alcohol SA (0.19 ml of 12 % alcohol (w/v)/delivery) and then receive separate alcohol (8%, w/v) and nicotine (15μg/kg/infusion) SA sessions on the same day ("daily dual access"). Animals then receive access to alcohol and then to nicotine (or in the reverse order) in alternating 5-min periods in 2-h sessions ("alternating access"). We then determine if alternating access modifies the effects of naltrexone on responding for alcohol and nicotine. We found that with daily dual access, nicotine significantly increased alcohol SA when alcohol access occurred prior to nicotine access and that nicotine SA significantly decreased when the alcohol SA session preceded it. During alternating access, nicotine also significantly increased alcohol intake. Naltrexone (0.3 or 1mg/kg) significantly reduced alcohol SA during these alternating access sessions in animals that also received nicotine SA, but had minimal effects on animals receiving alcohol SA alone. Naltrexone did not affect nicotine SA under any condition. This sequential access procedure effectively models the effects of nicotine on alcohol intake noted in humans.

Nicotine Decreases Ethanol-Induced Dopamine Signaling and Increases Self-Administration via Stress Hormones

Tobacco smoking is a well-known risk factor for subsequent alcohol abuse, but the neural events underlying this risk remain largely unknown. Alcohol and nicotine reinforcement involve common neural circuitry, including the mesolimbic dopamine system. We demonstrate in rodents that pre-exposure to nicotine increases alcohol self-administration and decreases alcohol-induced dopamine responses. The blunted dopamine response was due to increased inhibitory synaptic transmission onto dopamine neurons. Blocking stress hormone receptors prior to nicotine exposure prevented all interactions with alcohol that we measured, including the increased inhibition onto dopamine neurons, the decreased dopamine responses, and the increased alcohol self-administration. These results indicate that nicotine recruits neuroendocrine systems to influence neurotransmission and behavior associated with alcohol reinforcement.