Previous work with Sprague-Dawley (SD) rats indicated that subjecting these rats to multiple episodes of ethanol diet could provoke anxiety-like responses. Because alcohol-preferring P rats have been reported to have neurochemical alterations in many systems shown to modulate anxiety-like responses, P rats were compared to SD rats. Rats were subjected to one or three cycles of 5 days’ exposure to 4.5% or 7% ethanol diet to assess anxiety-like behavior.
- The mean number of days abstinent and mean number of heavy drinking days were calculated for those patients who were not abstinent at six months.
- By incorporating various experimental manipulations that entail modifying genetic and/or environmental factors, these models have generally overcome the natural tendency for rodents to either avoid alcohol or consume it in limited amounts that typically do not produce signs of intoxication.
- Findings thus far indicate that only the P line of rats meets all the criteria established for a valid animal model of alcoholism, with progress having been made in characterizing the AA, HAD and sP lines of rats.
- Increasingly, individuals with alcohol use disorder (AUD) seek and provide support for relapse prevention in text-based online environments such as discussion forums.
Role of CRF in Stress Associated With Alcohol Dependence and Withdrawal
Although the circumstances and manner in which stress influences drinking behavior are complex and not fully understood, it generally is acknowledged that stressful life events prominently influence alcohol drinking and, in particular, may trigger relapse (Brady and Sonne 1999; Sillaber and Henniger 2004; Sinha 2001; Weiss 2005). Activation of the HPA axis and CRF-related brain stress circuitry resulting from alcohol dependence likely contributes to amplified motivation to drink. For example, animal studies have indicated that elevation of corticosteroid hormone levels may enhance the propensity to drink through an interaction with the brain’s main reward circuitry (i.e., mesocorticolimbic dopamine system) (Fahlke et al. 1996; Piazza and Le Moal 1997). A CRF antagonist that acts on both the CRF1 and CRF2 receptors (i.e., a nonselective peptide CRF antagonist) called D-Phe-CRF12–42 reduced excessive drinking in dependent animals when administered into the brain ventricles (Finn et al. 2007; Valdez et al. 2002) or the central nucleus of the amygdala (Funk et al. 2006).
Severity of Alcohol Dependence Questionnaire (SADQ) (20 items)36 was developed to study the severity of alcohol dependence. Scores 0–3 represent no dependence, 4–19 mild dependence, 20–30 moderate dependence, 31–44 severe dependence, and 45+ very severe dependence. Participants provided demographic information including gender, age, race, education, and marital status. Questions about smoking and smoking history included current cigarettes per day (CPD), age of smoking onset, and whether participants had wanted to cut down or quit using tobacco during the past 12 months (Yes/No). Participants completed assessments (i.e., interviews and questionnaires) prior to treatment (baseline), the end of treatment (twelve weeks), and three, six, nine, and twelve months after treatment had ended. The baseline and follow-up evaluations both utilized the Timeline Follow-Back (Sobell and Sobell, 1992), which gauged drinking behavior and included questionnaires that measured drinking consequences, other drug use, and general psychosocial functioning.
However, recent work has suggested that more persistent effects may be obtained when experimental parameters used in the model are optimized for facilitating the negative reinforcing effects of alcohol. More specifically, recognizing the stressful nature of the procedure (Ford, Steele, McCracken, Finn, & Grant, 2013; López-Grancha et al., 2006), it has been suggested that the time interval in which food is delivered in the model may be a key factor in establishing the negative reinforcing effects of alcohol. Of note, the schedule-induced polydipsia procedure has been employed to induce alcohol self-administration in non-human primates where a percent of the animals continue to engage in excessive drinking behavior following the removal of the schedule (Grant et al., 2008). Although topiramate is not currently approved for the treatment of alcohol dependence 27, several randomized double-blind placebo-controlled trials have demonstrated its efficacy in improving drinking behaviour and maintaining abstinence28-30.
Howard C Becker
The resulting depolarization causes vesicles containing stored neurotransmitter molecules to fuse with the cell membrane and release their contents into the synaptic cleft. Each neuron produces and releases only one or a few types of neurotransmitters but carries receptors for several different types of neurotransmitters on its surface. Renewed discussion of the stabe reduction (but not elimination) of alcohol consumption has followed the recent demonstration that nalmefen, an opioid modulator, is effective for this purpose.
Six-month course and outcome of treatment-seeking individuals with alcohol dependence syndrome
- Clinicians may also need to work with patients to recognize, differentiate, and manage symptoms relating to withdrawal and Axis I disorders.
- The specific composition of a given receptor molecule determines its distinct physiological and pharmacological properties.
- Symptoms of depression and anxiety were assessed with the Hamilton Depression Rating Scale (HDRS) 21 and the Hamilton Anxiety Rating Scale (HARS) 22.
Subsequently, this observation has been repeated in many other systems, including the cerebral cortex, NAc, amygdala, and VTA (Hoffman 2003). These investigations further demonstrated that ethanol inhibition of NMDAR activation is non-competitive with glutamate—that is, the ethanol molecules do not compete with and displace glutamate molecules from the NMDAR; instead, receptor activation is reduced even though glutamate still binds to it. Because the influx of cations through iGluRs during excitatory neurotransmission is critical for inducing plasticity, it is not surprising that acute ethanol exposure negatively affects the induction of NMDA-dependent long-term potentiation as well as promotes long-term depression (Blitzer et al. 1990; Hendricson et al. 2002). The motivation to drink less, and the opportunity to treat harmful alcohol use and alcohol dependence, often arise not only from the medical consequences of excessive drinking, but also from its social side effects (loss of driver’s license, disruption of marriage or other relationship, loss of job). The annual cost to the nation of problematic alcohol consumption have been estimated at 25.4 billion euros (e4). Thus, alcohol use is one of the main avoidable risk factors for disease and premature death, as well as a major source of health-care costs and social problems (crimes committed under the influence of alcohol, alcohol-related traffic accidents, etc.).
Difficulties in emotion regulation on the subscale “Emotional clarity” were observed also in patients with a high level of craving at discharge (Figure 3). Correlations during the period of early abstinence were present between DERS and psychological variables of CBA-OE, PAMS and NAMS (Table 4). Relapse represents a major challenge to treatment efforts for people suffering from alcohol dependence. To date, no therapeutic interventions can fully prevent relapse, sustain abstinence, or temper the amount of drinking when a “slip” occurs.
Although some researchers have proposed that ethanol binds directly to GABAA receptors (Wick et al. 1998), the variability of results suggests that alcohol affects receptor function more indirectly (e.g., via phosphorylation events). This hypothesis is supported by observations that when phosphorylation is prevented by inhibiting PKC, the receptors’ sensitivity to ethanol is reduced (Weiner et al. 1994). Similarly, some studies found that receptors obtained from mice that lack a certain PKC variant were less sensitive to ethanol than receptors from normal mice (Bowers et al. 1999; Harris et al. 1995; Weiner et al. 1994). However, receptors from mice that lack another PKC variant, or from mice in which that PKC variant is inhibited, showed increased sensitivity to ethanol and benzodiazepine potentiation (Hodge et al. 1999; Proctor et al. 2003; Qi et al. 2007).
MANAGEMENT OF MINOR ALCOHOL WITHDRAWAL SYNDROME
The agent acamprosate, which has prolonged abstinence in alcohol-dependent patients in some studies (see Kranzler and Gage 2008) and is approved for the treatment of alcohol dependence in the United States, appears to act on both NMDA and mGluR5 receptors (Spanagel and Kiefer 2008). Thus, acamprosate inhibits NMDAR-mediated calcium influx in cultured rat neurons from some, but not all, brain regions (Allgaier et al. 2000; Popp and Lovinger 2000). Moreover, acamprosate recently was shown to inhibit mGluR5 signaling (Harris et al. 2003) and is ineffective in mice lacking mGluR5 (Blednov and Harris 2008). In general, acamprosate appears to restore the balance between excitatory (i.e., glutamate) and inhibitory (i.e., GABA) neuro-transmission following chronic alcohol consumption and withdrawal (De Witte et al. 2005).
This latter shortcoming, however, has been recently addressed in studies incorporating repeated periods of deprivation along with concurrent access to several alcohol concentrations (rather than a single choice vs. water) (Rodd et al., 2003, 2009; Spanagel & Hölter, 2000). These procedural manipulations have yielded more robust and durable alcohol deprivation effects. The paper presented from Dr. Spanagel’s lab highlights these effects in the alcohol deprivation model along with other characteristics that suggest the model may reflect compulsive aspects of alcohol addiction. The dopamine system, which as described above is controlled at least in part by the opioid system, plays an important role in alcohol withdrawal. Studies in which alcohol was withheld for 8 hours from rats that had ingested alcohol in a liquid diet for several weeks suggest that dopamine release in the NAc is reduced during acute alcohol withdrawal but returns to control levels if the animals are allowed to self-administer alcohol (Weiss et al. 1996).
Such models also are crucial for identifying new potential therapeutic targets and evaluating efficacy and safety of various treatment strategies. It is well established that alcohol use has many harmful effects on physical and psychological health. However, the course of alcohol dependence is often characterized by periods of abstinence with recurring periods of relapses. Impulsive and compulsive behaviours play a crucial role in alcohol abuse, craving and relapse 39-41; therefore, medications with anticraving properties have been used for prevention of relapse. Several studies have demonstrated topiramate’s efficacy in the management of impulsive, aggressive and self-harmful behaviour 42, gambling 43, eating disorders 44, as well as an adjunct to SSRIs in obsessive-compulsive disorder 45.
Effects of Ethanol Exposure on Opiate Systems
Moreover, there is evidence that norepinephrine and CRF systems in the brain not only interact closely to mediate behavioral responses to stress, but also play an important role in negative affective states and relapse vulnerability during alcohol/drug abstinence (Dunn and Swiergiel 2008; Smith and Aston-Jones 2008). Thus, chronic alcohol exposure and withdrawal experiences alcohol dependence, withdrawal, and relapse pmc can be viewed as potent stressors that disrupt the functional integrity of the HPA axis as well as recruit extrahypothalamic CRF and other brain stress systems. This perturbation in brain and neuroendocrine stress systems may have significant implications regarding motivation for alcohol self-administration.
Endogenous opioids, however, can act on μ receptors on the GABAergic neurons, thereby inhibiting GABA transmission, and ultimately leading to increased dopamine release. A) Acute alcohol can induce β-endorphin release, resulting in activation of μ receptors on the GABAergic neurons in VTA. This, in combination with alcohol’s inhibition of glutamate effects on GABA neurons, could lead to decreased GABAergic activity in the VTA, and subsequently increased firing of the dopaminergic neurons, resulting in increased dopamine release in the nucleus accumbens (NAc). B) During withdrawal from alcohol, after chronic alcohol exposure that produces alcohol dependence (i.e., in the absence of alcohol in a dependent individual), glutamate input to GABA neurons is increased, leading to decreased dopamine release.