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The GABA system and addiction 

The GABA system and addiction
Chapter:
The GABA system and addiction
Source:
Addiction (Oxford Psychiatry Library)
Author(s):

Professor David J. Nutt

and Dr Liam J. Nestor

DOI:
10.1093/med/9780199685707.003.0008

Key points

  • GABA is the major inhibitory neurotransmitter in the brain.

  • GABA binds with GABAA and GABAB receptors to inhibit neuronal activity.

  • Substances of abuse can downregulate or upregulate the GABA system.

  • GABAB receptors modulate substance reward and reinforcement behaviours.

  • Disturbances to the GABA system may predate substance addiction.

  • Compounds that target the GABA system may help in the treatment of addiction.

Substances of addiction impinge upon, and disrupt, a variety of neurotransmitter systems in the brain. Research has recently pointed to the potential role of gamma-aminobutyric acid (GABA) in substance abuse and dependence (see Figure 8.1). GABA is the major inhibitory neurotransmitter in the brain. Deficits in the functioning of this system may alter its efficacy to modulate other neurotransmitter systems (e.g. dopamine), which are strongly implicated in substance addiction.

Figure 8.1 Major GABA pathways in the human brain. GABA exerts its inhibitory effect on other neurotransmitter systems, mainly through GABAergic interneurons

Figure 8.1
Major GABA pathways in the human brain. GABA exerts its inhibitory effect on other neurotransmitter systems, mainly through GABAergic interneurons

In this chapter, we will discuss the potential role of GABA in substance addiction and the potential value of compounds that target this system in the treatment and management of substance use disorders.

8.1 The GABA system

GABAergic inhibition is seen at all levels of the brain, including the hypothalamus, hippocampus, frontal cortex, nucleus accumbens (NAcc), and cerebellum. As well as the large well-established GABA pathways, GABA interneurons are abundant in the brain, with ~50% of all inhibitory synapses in the brain mediated by GABA.

GABA is synthesized from glutamate and, when released, binds with two types of receptors. The first are ionotropic GABAA receptors that contain chloride ion channels. These receptors predominately mediate rapid inhibitory neurotransmission throughout the brain via an influx of chloride ions (see Figure 8.2).

Figure 8.2 The neurochemistry of GABA, showing (1) the synthesis of GABA from glutamate (via glutamic acid decarboxylase; (2) transport and storage of GABA in the vesicle; (3) the release of GABA by exocytosis; (4) binding to ionotropic GABAA receptors and the influx of chloride ions (Clˉ) that hyperpolarize the nerve cell; (5) binding to metabotropic GABAB receptors and subsequent downstream effects mediated via a G-protein and/or cAMP to K+ and Na+ channels; and (6) the reuptake of synaptic GABA into the presynaptic nerve terminal.

Figure 8.2
The neurochemistry of GABA, showing (1) the synthesis of GABA from glutamate (via glutamic acid decarboxylase; (2) transport and storage of GABA in the vesicle; (3) the release of GABA by exocytosis; (4) binding to ionotropic GABAA receptors and the influx of chloride ions (Clˉ) that hyperpolarize the nerve cell; (5) binding to metabotropic GABAB receptors and subsequent downstream effects mediated via a G-protein and/or cAMP to K+ and Na+ channels; and (6) the reuptake of synaptic GABA into the presynaptic nerve terminal.

Chloride ion influx hyperpolarizes the neuron cell membrane—it induces neuronal inhibition. GABAA receptors consist of several glycoprotein subunits (or binding sites). Substances, such as benzodiazepines, barbiturates, steroids, alcohol, and general anaesthetics, have different affinities for these subunits. GABA also activates a class of metabotropic GABAB receptors (see Figure 8.2). GABAB receptors are located on both pre- and postsynaptic neurons: presynaptic receptors typically inhibit the release of other neurotransmitters whereas postsynaptic receptors are excitatory. GABAB receptors are thought to modulate a variety of substance use-related reward and reinforcement behaviours.

GABA exerts its inhibitory effect on other neurotransmitter systems, mainly through GABAergic interneurons. For example, interneurons in the ventral tegmental area (VTA) are a primary inhibitory regulator of dopamine neurons projecting to the ventral striatum (VS). Substances that inhibit these interneurons, such as heroin at the mu opioid receptor, therefore, reduce GABAergic inhibition of VTA dopamine neuron projections to the VS. Moreover, a subset of GABAergic medium spiny neurons in the VS send reciprocal projections back to the VTA—a projection that mediates inhibitory feedback on dopamine neuron activity via GABAB receptors.

Medium spiny GABAergic neurons are also the principal projection neurons of the striatum. They receive excitatory glutamatergic inputs from the cerebral cortex and thalamus and modulatory dopaminergic innervation from the midbrain VTA. Striatopallidal medium spiny neurons express the dopamine 2 receptor (D2R) whereas striatonigral medium spiny neurons express the dopamine 1 receptor (D1R). These two sets of GABAergic neurons are homogenously distributed throughout the striatum and are known to have opposing behavioural effects—striatonigral is part of the ‘direct pathway’, and the striatopallidal is part of the ‘indirect pathway’.

Therefore, the GABA systems within midbrain and striatal regions are well placed to accommodate the modulating effects of substances of addiction and the potential of medications to modify activity in these regions during treatment.

8.2 Substance addiction

There are a number of abused substances that boost GABA functioning. These are typically the sedative or ‘downer’ substances, such as alcohol, benzodiazepines, gammahydroxybutyrate (GHB), and barbiturates—all enhance the actions of GABA at the GABAA receptor to sedate the brain. Evidence suggests, however, that stimulants may also influence GABA functioning indirectly, perhaps sensitizing the GABA system following chronic use (see Figure 8.3).

Figure 8.3 Increased GABA sensitivity in cocaine abusers. Regional changes in metabolism induced by lorazepam in control and cocaine-abusing subjects. Lorazepam-induced decrements in regional brain glucose metabolism were significantly larger in the cocaine-abusing group than in the comparison group (bt >2.8, df = 25, p <0.01; post hoc t tests) (Volkow, N. D., Wang, G. J., Fowler, J. S., Hitzemann, R., Gatley, S. J., Dewey, S. S., & Pappas, N. (1998). Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study. Am J Psychiatry, 155(2), 200–206). Reprinted with permission from the American Journal of Psychiatry,

Figure 8.3
Increased GABA sensitivity in cocaine abusers. Regional changes in metabolism induced by lorazepam in control and cocaine-abusing subjects. Lorazepam-induced decrements in regional brain glucose metabolism were significantly larger in the cocaine-abusing group than in the comparison group (bt >2.8, df = 25, p <0.01; post hoc t tests) (Volkow, N. D., Wang, G. J., Fowler, J. S., Hitzemann, R., Gatley, S. J., Dewey, S. S., & Pappas, N. (1998). Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study. Am J Psychiatry, 155(2), 200–206). Reprinted with permission from the American Journal of Psychiatry,

(Copyright ©2006). American Psychiatric Association. All Rights Reserved.

The α‎5 subtype of the GABA-benzodiazepine receptor is thought to play a prominent and specific role in the reinforcing effects of alcohol. This is due to its distribution in striatal regions of the brain and the efficacy of agonists and antagonists to increase and decrease, respectively, alcohol self-administration in animals. The α‎5 subtype is significantly lower in the nucleus accumbens (NAc)/VS of abstinent alcoholics (see Figure 8.4) as well as in the hippocampus and amygdala. This finding may suggest the α‎5 subtype downregulates in limbic brain regions in order to compensate for the chronic effects of alcohol. Benzodiazepine receptor distribution is also significantly lower in frontal regions of the brain in alcoholics. These results in alcoholism and cocaine addiction may point to the opposing long-term effects of these substances on GABA functioning.

Figure 8.4 Reduced striatal GABA benzodiazepine receptors in alcoholics, showing the spread of the α‎5 GABA-benzodiazepine receptor subtype in the left and right nucleus accumbens (NAc) in abstinent alcoholic patients and controls. Originally published in Lingford-Hughes, A., Reid, A. G., Myers, J., Feeney, A., Hammers, A., Taylor, L. G., Rosso, L., Turkheimer, F., Brooks, D. J., Grasby, P., & Nutt, D. J. (2010). A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced alpha5 benzodiazepine receptors in limbic regions. J Psychopharmacol, 26(2), 273–281.

Figure 8.4
Reduced striatal GABA benzodiazepine receptors in alcoholics, showing the spread of the α‎5 GABA-benzodiazepine receptor subtype in the left and right nucleus accumbens (NAc) in abstinent alcoholic patients and controls. Originally published in Lingford-Hughes, A., Reid, A. G., Myers, J., Feeney, A., Hammers, A., Taylor, L. G., Rosso, L., Turkheimer, F., Brooks, D. J., Grasby, P., & Nutt, D. J. (2010). A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced alpha5 benzodiazepine receptors in limbic regions. J Psychopharmacol, 26(2), 273–281.

8.3 Treatment

The benzodiazepines, such as diazepam, are the most commonly used compounds for managing alcohol withdrawal. Their long-term use, however, is not recommended, given their interaction with alcohol and their abuse potential. Research suggests that baclofen (30 mg/day), a selective GABAB receptor agonist, may be as effective as diazepam for alcohol withdrawal (see Figure 8.5).

Figure 8.5 Baclofen reduces alcohol withdrawal. Score of the Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) scale in patients treated for 10 consecutive days with baclofen (30 mg/day) and diazepam (0.5–0.75 mg/kg/day on days 1–6, tapering the dose by 25% daily from day 7 to day 10. CIWA-Ar administration occurred once a day, on days 1, 2, 3, 4, 5, and 10, immediately before the first daily administration of drugs (scoring of day 1 is baseline). Reprinted from Am J Med, 119(3), Addolorato, G., Leggio, L., Abenavoli, L., et al. Baclofen in the Treatment of Alcohol Withdrawal Syndrome: A Comparative Study vs Diazepam, 276, e213–278.

Figure 8.5
Baclofen reduces alcohol withdrawal. Score of the Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) scale in patients treated for 10 consecutive days with baclofen (30 mg/day) and diazepam (0.5–0.75 mg/kg/day on days 1–6, tapering the dose by 25% daily from day 7 to day 10. CIWA-Ar administration occurred once a day, on days 1, 2, 3, 4, 5, and 10, immediately before the first daily administration of drugs (scoring of day 1 is baseline). Reprinted from Am J Med, 119(3), Addolorato, G., Leggio, L., Abenavoli, L., et al. Baclofen in the Treatment of Alcohol Withdrawal Syndrome: A Comparative Study vs Diazepam, 276, e213–278.

Copyright (2006), with permission from Elsevier.

There are also concerns regarding interactions between benzodiazepines and opioid medications (e.g. methadone and buprenorphine). Benzodiazepines and opiates interact to induce increased levels of subjective effects (i.e. abuse potential) and sedation (see Figure 8.6). Benzodiazepines are also frequently identified at autopsy in methadone-related deaths.

Figure 8.6 Pharmacodynamic interactions of diazepam with opiates. Visual analogue scale ratings (0–100 mm) of sedation (not sedated–very sedated) and liking of drug effect (dislike very much–like very much), following administration of either 0 mg diazepam (0 mg DIAZ) or 40 mg diazepam (40 mg DIAZ), in combination with either 100% or 150% of the normal maintenance opioid dose (100% OP/150% OP) of methadone or buprenorphine. Data are expressed as mean ± SEM. Reprinted from Drug Alcohol Depend, 91(2–3), Lintzeris, N., Mitchell, T. B., Bond, A. J., et al. Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients, 187–194,

Figure 8.6
Pharmacodynamic interactions of diazepam with opiates. Visual analogue scale ratings (0–100 mm) of sedation (not sedated–very sedated) and liking of drug effect (dislike very much–like very much), following administration of either 0 mg diazepam (0 mg DIAZ) or 40 mg diazepam (40 mg DIAZ), in combination with either 100% or 150% of the normal maintenance opioid dose (100% OP/150% OP) of methadone or buprenorphine. Data are expressed as mean ± SEM. Reprinted from Drug Alcohol Depend, 91(2–3), Lintzeris, N., Mitchell, T. B., Bond, A. J., et al. Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid dependent patients, 187–194,

Copyright (2007), with permission from Elsevier.

Research has also tested the potential efficacy of GABA compounds to reduce relapse and attenuate the acute reinforcing effects of substances—thereby suggesting a potential role for GABA in substance abuse and dependence treatment (see Table 8.1). Baclofen, the GABAB agonist, has also proven potentially efficacious in preventing alcohol lapse and relapse in alcoholics with liver cirrhosis (see Figure 8.7).

Table 8.1 GABA-modulating compounds that have been tested as potential treatments for substance addiction. GAD, glutamate decarboxylase; GABA-T, GABA-transaminase.

Medication

Mechanism of action

Addiction type

Efficacy

Baclofen

GABAB agonist

Alcohol

Suppresses alcohol withdrawal syndrome

Produces a decrease in alcohol craving when prescribed with no superior limit of dose

Shows a dose-effect relationship in reducing alcohol use

Associated with a significant reduction in state anxiety in alcoholics

Well tolerated and safe when given in combination with intoxicating doses of alcohol

Cocaine

Attenuates cocaine relapse in baboons

May reduce some positive reinforcing effects of cocaine when combined with amantadine

Reduces self-administration of cocaine

Reduces craving in methadone-maintained patients also dependent on cocaine

Methamphetamine

May have a small treatment effect relative to placebo

Tiagabine

GABA reuptake inhibitor

Alcohol

May be effective in alcohol dependence when combined with standard psychotherapy

Cocaine

Does not attenuate cocaine relapse in baboons

Attenuates craving and some of the reinforcing effects of acute cocaine administration

Reduces cocaine-taking compared to placebo or gabapentin in methadone-maintained users

Dose of 20 mg/day does not robustly decrease cocaine use

Does not alter the effects of oral cocaine

Topiramate

GABAA agonist?

Alcohol

Reduces alcohol craving and increases alcohol abstinence

Potential efficacy for relapse prevention

May be superior to naltrexone in reducing alcohol craving

May reduce subjective effects of alcohol more than alcohol craving

Up to 300 mg/d superior to placebo in lessening dependence severity and harmful drinking

Cocaine

May be effective in promoting cocaine abstinence

Methamphetamine

Does not appear to promote abstinence but can reduce amount of methamphetamine used

May enhance, rather than attenuate, the positive subjective effects of methamphetamine

Valproate

GAD inducer and inhibitor of GABA-T

Cocaine

Does not reduce spontaneous and cue-induced cocaine craving

Vigabatrin

Inhibitor of GABA-T

Cocaine

Short-term use may increase abstinence from cocaine

Methamphetamine

Not efficacious in attenuating the positive subjective effects of methamphetamine in the laboratory

Figure 8.7 Baclofen reduces relapse risk in alcoholics. Survival analysis of proportion of lapse and relapse in alcoholics. Number at risk refers to proportion remaining free of lapse and relapse. Cumulative abstinence duration was about twofold higher in patients allocated to baclofen than in those assigned to placebo (mean 62·8 ± 5·4] vs 30·8 ± 5.5 days; p = 0·001). No hepatic side effects were recorded. Reprinted from The Lancet, 370(9603), Addolorato, G., Leggio, L., Ferrulli, A. et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study, 1915–1922.,

Figure 8.7
Baclofen reduces relapse risk in alcoholics. Survival analysis of proportion of lapse and relapse in alcoholics. Number at risk refers to proportion remaining free of lapse and relapse. Cumulative abstinence duration was about twofold higher in patients allocated to baclofen than in those assigned to placebo (mean 62·8 ± 5·4] vs 30·8 ± 5.5 days; p = 0·001). No hepatic side effects were recorded. Reprinted from The Lancet, 370(9603), Addolorato, G., Leggio, L., Ferrulli, A. et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study, 1915–1922.,

Copyright (2007), with permission from Elsevier.

Tiagabine is a GABA reuptake inhibitor—its mechanism of action makes more GABA available for synaptic transmission (see (6) on Figure 8.2). Tiagabine has been reported to attenuate craving and some of the subjective effects of iv cocaine (see Figure 8.8). Results suggest that it does not attenuate the effects of oral cocaine, however.

Figure 8.8 Tiagabine reduces the effects of cocaine. Tiagabine effects on average subjective responses, using the Cocaine Effects Questionnaire (CEQ), to iv saline and two escalating doses of cocaine (0.15 and 0.3 mg/kg), given 30 min apart. The measurements were obtained 4.5 min before and 2.5, 10, and 15 min after saline and cocaine administration. Data shown are the average values (SEM) and significant group difference (p <0.05) for craving and stimulated. Reprinted from Pharmacol Biochem Behav, 82(3), Sofuoglu, M., Poling, J., Mitchell, E., & Kosten, T. R., Tiagabine affects the subjective responses to cocaine in humans, 569–573.

Figure 8.8
Tiagabine reduces the effects of cocaine. Tiagabine effects on average subjective responses, using the Cocaine Effects Questionnaire (CEQ), to iv saline and two escalating doses of cocaine (0.15 and 0.3 mg/kg), given 30 min apart. The measurements were obtained 4.5 min before and 2.5, 10, and 15 min after saline and cocaine administration. Data shown are the average values (SEM) and significant group difference (p <0.05) for craving and stimulated. Reprinted from Pharmacol Biochem Behav, 82(3), Sofuoglu, M., Poling, J., Mitchell, E., & Kosten, T. R., Tiagabine affects the subjective responses to cocaine in humans, 569–573.

Copyright (2005), with permission from Elsevier.

Tiagabine may also be more clinically effective than placebo or gabapentin in reducing cocaine use in methadone-maintained cocaine abusers (see Figure 8.9). For alcohol dependence, tiagabine has shown some efficacy when combined with standard psychotherapy.

Figure 8.9 Tiagabine reduces cocaine use in methadone-maintained cocaine abusers. (A) Change of the percentage of cocaine-free urines per week by treatment groups. (B) Change of cocaine-abstinent rates per week by treatment groups. (C) Fitted probability of presenting any cocaine-free urine per week among the different treatment groups. This is calculated from mixed-effect ordinal regression analysis models that controlled for the baseline cocaine-free urines and that included years of cocaine and heroin use as covariates. Difference between tiagabine and gabapentin groups (Z = –2.48, d.f. = 1, p = 0.01). Difference between tiagabine and placebo groups (Z = 3.90, d.f. = l, p = 0.0001). Reprinted from Drug Alcohol Depend, 87(1), Gonzalez, G., Desai, R., Sofuoglu, et al. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients, 1–9.

Figure 8.9
Tiagabine reduces cocaine use in methadone-maintained cocaine abusers. (A) Change of the percentage of cocaine-free urines per week by treatment groups. (B) Change of cocaine-abstinent rates per week by treatment groups. (C) Fitted probability of presenting any cocaine-free urine per week among the different treatment groups. This is calculated from mixed-effect ordinal regression analysis models that controlled for the baseline cocaine-free urines and that included years of cocaine and heroin use as covariates. Difference between tiagabine and gabapentin groups (Z = –2.48, d.f. = 1, p = 0.01). Difference between tiagabine and placebo groups (Z = 3.90, d.f. = l, p = 0.0001). Reprinted from Drug Alcohol Depend, 87(1), Gonzalez, G., Desai, R., Sofuoglu, et al. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients, 1–9.

Copyright (2007), with permission from Elsevier.

Topiramate is an anti-epileptic that is thought to act as an agonist at GABAA receptors. Research has additionally demonstrated its potential clinical efficacy in substance addiction. Long-term outcomes for alcohol abstinence appear to be better for topiramate compared to placebo treatment (see Figure 8.10). Topiramate also significantly increases cocaine abstinence compared to placebo, suggesting a potential clinical effect in cocaine-dependent populations.

Figure 8.10 Topiramate increases abstinence from alcohol. The cumulative probability function of reaching 16 weeks of abstinence by group. Although 67 patients in total (78.8%) had relapsed to alcohol use by the end of the study (16 weeks after discharge), relapse rate was significantly lower in the topiramate group (66.7%) compared with the control group (85.5%) (p <0.05). Also, median duration of abstinence in the topiramate group was significantly longer compared to the non-medicated group (10 weeks vs 4 weeks; log rank test, p <0.01). Cox proportional hazard model showed that risk of relapse was 56% lower among patients receiving topiramate compared to controls (HR = 0.515, 95% CI: 0.304–0.874, p <0.05). Reproduced from Paparrigopoulos, T., Tzavellas, E., Karaiskos, D., Kourlaba, G., & Liappas, I. (2011). Treatment of alcohol dependence with low-dose topiramate: an open-label controlled study. BMC Psychiatry, 11, 41.

Figure 8.10
Topiramate increases abstinence from alcohol. The cumulative probability function of reaching 16 weeks of abstinence by group. Although 67 patients in total (78.8%) had relapsed to alcohol use by the end of the study (16 weeks after discharge), relapse rate was significantly lower in the topiramate group (66.7%) compared with the control group (85.5%) (p <0.05). Also, median duration of abstinence in the topiramate group was significantly longer compared to the non-medicated group (10 weeks vs 4 weeks; log rank test, p <0.01). Cox proportional hazard model showed that risk of relapse was 56% lower among patients receiving topiramate compared to controls (HR = 0.515, 95% CI: 0.304–0.874, p <0.05). Reproduced from Paparrigopoulos, T., Tzavellas, E., Karaiskos, D., Kourlaba, G., & Liappas, I. (2011). Treatment of alcohol dependence with low-dose topiramate: an open-label controlled study. BMC Psychiatry, 11, 41.

Vigabatrin (γ‎-vinyl GABA) is an anti-epileptic. Vigabatrin irreversibly inhibits GABA-transaminase (GABA-T), the principal enzyme responsible for the breakdown of synaptic GABA. Vigabatrin has been shown to rapidly elevate GABA concentrations in humans. Vigabatrin blocks cocaine-induced dopamine release in the VS and appears to prevent the behavioural manifestations of cocaine dependence in animals. Compared to placebo, vigabatrin has been shown to increase rates of abstinence in cocaine-dependent volunteers (see Figure 8.11). While vigabatrin has not proved efficacious in attenuating the positive subjective effects of methamphetamine in the laboratory, its use in promoting methamphetamine abstinence has yet to be tested.

Figure 8.11 Vigabatrin increases cocaine abstinence. Kaplan–Meier cumulative probability distributions of onset of full end-of-trial abstinence for cocaine-dependent individuals randomly assigned to vigabatrin or placebo. Probability estimates of full end-of-trial abstinence onset were 0.33 for the vigabatrin group and 0.09 for the placebo group, and these differed significantly (p≤ 0.02). Weekly abstinence did not differ over the entire treatment phase, but differences favouring vigabatrin were found at weeks 7 (p≤ 0.02) and 9 (p≤ 0.02) (Brodie, J. D., Case, B. G., Figueroa, E., Dewey, S. L., Robinson, J. A., Wanderling, J. A., & Laska, E. M. (2009). Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry, 166(11), 1269–1277.). Reprinted with permission from the American Journal of Psychiatry,

Figure 8.11
Vigabatrin increases cocaine abstinence. Kaplan–Meier cumulative probability distributions of onset of full end-of-trial abstinence for cocaine-dependent individuals randomly assigned to vigabatrin or placebo. Probability estimates of full end-of-trial abstinence onset were 0.33 for the vigabatrin group and 0.09 for the placebo group, and these differed significantly (p≤ 0.02). Weekly abstinence did not differ over the entire treatment phase, but differences favouring vigabatrin were found at weeks 7 (p≤ 0.02) and 9 (p≤ 0.02) (Brodie, J. D., Case, B. G., Figueroa, E., Dewey, S. L., Robinson, J. A., Wanderling, J. A., & Laska, E. M. (2009). Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry, 166(11), 1269–1277.). Reprinted with permission from the American Journal of Psychiatry,

(Copyright ©2006). American Psychiatric Association. All Rights Reserved.

8.4 Conclusion

GABA is the major inhibitory neurotransmitter in the brain. GABAergic interneurons and GABA projection neurons are located in dopamine midbrain and striatal regions. These regions are important in the reinforcing effects of substances of abuse. GABA is exploited by substances of abuse, such as alcohol and benzodiazepines, which may result in a downregulation of the GABA system. Stimulants, however, may sensitize the GABA system. Therefore, the chronic abuse of substances may alter the balance of GABA functioning. Disturbances in the GABA system, however, may predate substance abuse and addiction.

Medications that boost the availability of GABA or mimic its effects at receptors may possess some clinical potential with respect to abstinence or in attenuating the acute reinforcing effects of substances. Attenuating the reinforcing effects of substances may reduce their use. GABAergic compounds, such as benzodiazepines, significantly interact with certain opioid medications to increase their reinforcing and sedative effects, however.

References and Further Reading

Addolorato G, Caputo F, Capristo E, et al. (2002). Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol and Alcoholism, 37, 504–8.Find this resource:

    Addolorato G, Leggio L, Abenavoli L, et al. (2006). Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study vs diazepam. American Journal of Medicine, 119, 276. e13–18.Find this resource:

      Addolorato G, Leggio L, Ferrulli A, et al. (2007). Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet, 370, 1915–22.Find this resource:

        Brodie JD, Case BG, Figueroa E, et al. (2009). Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. American Journal of Psychiatry, 166, 1269–77.Find this resource:

          Chick J, & Nutt DJ. (2012). Substitution therapy for alcoholism: time for a reappraisal? J Psychopharmacol, 26(2), 205–212.Find this resource:

            Gonzalez G, Desai R, Sofuoglu M, et al. (2007). Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine-dependent methadone-treated patients. Drug and Alcohol Dependence, 87, 1–9.Find this resource:

              Lingford-Hughes A, Reid vAG, Myers J, et al. (2010). A [11C]Ro15 4513 PET study suggests that alcohol dependence in man is associated with reduced alpha5 benzodiazepine receptors in limbic regions. Journal of Psychopharmacology, 26, 273–81.Find this resource:

                Lintzeris N, Mitchell TB, Bond AJ, Nestor L and Strang J (2007). Pharmacodynamics of diazepam co-administered with methadone or buprenorphine under high dose conditions in opioid-dependent patients. Drug and Alcohol Dependence, 91, 187–94.Find this resource:

                  Paparrigopoulos T, Tzavellas E, Karaiskos D, Kourlaba G and Liappas I (2011). Treatment of alcohol dependence with low-dose topiramate: an open-label controlled study. BMC Psychiatry, 11, 41.Find this resource:

                    Sofuoglu M, Poling J, Mitchell E and Kosten TR (2005). Tiagabine affects the subjective responses to cocaine in humans. Pharmacology Biochemistry and Behavior, 82, 569–73.Find this resource:

                      Volkow ND, Wang GJ, Fowler JS, et al. (1998). Enhanced sensitivity to benzodiazepines in active cocaine-abusing subjects: a PET study. American Journal of Psychiatry, 155, 200–6.Find this resource:

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