The role of glutamate neurotransmission in the

neuroadaptations of benzodiazepine

dependence, tolerance, and withdrawal.

Eric J. Nordstrom

Department of Pharmacology University of MinnesotaMinneapolis Medical Research FoundationHennepin County Medical Center

BACKGROUNDBenzodiazepines (BZ)• Classified as anxiolytics and/or anti-convulsants

• Have been in clinical practice for over 40 years

• Largely replaced barbiturates for anxiety-related disorders

• Dependence and/or tolerance emerges after chronic BZ administration

Neuropsychopharmacological Properties

The exact mechanism is unknown, but believed to be related to its ability to enhance the activity of GABA by altering the binding of GABA to the GABA A receptor while having no effect on the kinetics of channel opening and closing once GABA is bound.Typically administered orally

Onset and duration of action varies

Consequences of repeated BZ administration

• BZ dependence develops with long-term use, even at low to moderate doses

• This is characterized by tolerance to the pharmacological effects of BZs

• Upon cessation of BZ use, withdrawal symptoms arise (anxiety, tremor, etc. )

Neuroadaptive processes during chronic drug administration

• Chronic drug use may cause adaptive processes serving to counter the effects of the drug

• These processes are thought to persist after the drug has been cleared from the brain

• Thus, the residual neuroadaptations lacking opposition from the presence of drug may give rise to withdrawal symptoms

Koob & Bloom, 1988

Benzodiazepines and GABAergic mechanisms

Down regulation or loss of GABA A receptors from neuronal cell surface (which may involve degradation or recycling of the receptor), is thought to underlie the development of tolerance, and perhaps the emergence of withdrawal symptoms during chronic BZ administration

A more recent hypothesis suggests alterations in GABA A receptor subunit expression as a mechanism underlying receptor uncoupling and consequent reduction in GABA sensitivity

Luddens & Wisden, 1991

Allison et al., 2003

Alternative HypothesisCompensatory enhancement of glutamatergic mechanisms in response to, or counteract enhanced GABAergic activity induced by chronic BZ administration, leading to alteration between inhibitory and

excitatory balance

Consequences may include:• activation and/or upregulation of glutamatergic receptors leading to emergence of tolerance and withdrawal symptoms

FG 7142 and kindling: implications for chronic BZ agonist mechanisms

• Background• FG 7142 GABA A inverse agonist—reduces the ability of GABA to increase chloride channel conductance

• Known to be proconvulsant, induce anxiety, etc.

• Prolonged use leads to sensitisation of convulsant actions—know also as kindling.

FG 7142 and kindling: implications for chronic BZ agonist mechanisms

• BZ receptor agonists and inverse agonists both act at the same receptor (i.e., GABA A), but produce opposing effects when given repeatedly suggesting that the processes underlying BZ withdrawal and kindling might mirror each other

• However, studies failing to identify GABA A receptor alterations after inverse BZ agonist administration may suggest involvement of other mechanisms…

Another potential mechanism: Glutamate• FG 7142 administered together w/ anticonvulsant allowing FG 7142 to interact w/ receptor prevented kindling, indicating that the interaction of FG 7142 w/ GABA A receptor itself was not sufficient to induce kindling

• Pharmacological studies have demonstrated that NMDA antagonists (e.g., MK-801), but not AMPA antagonists can block GABA A inverse agonist induced-kindling

Stephans, 1995

Benzodiazepines and Glutamatergic mechanisms

Behavioral properties of BZs are shared by antagonists of glutamate receptors…

• NMDA antagonists (e.g., MK-801) used in animal models of anxiety have been shown to produce anxiolytic, anti-convulsant, and/or sedating effects after chronic BZ withdrawal.

• Studies w/ AMPA antagonists (e.g., NBQX) have shown prevention or reduction of the signs of dependence during chronic BZ administration.

These data suggest that excitatory receptor-dependent mechanisms may underlie the induction and expression of tolerance, dependence, and withdrawal symptoms during chronic BZ use.

Stephans et al., 1991; Lehmann et al., 1987

Neurochemical/Receptor

Binding Studies…During tolerance and withdrawal phases of chronic BZ use receptor binding assays have found:

• Increased MK-801 binding• Upregulation of NR1 and NR2B NMDA receptor subunit proteins

• Reduction in AMPA receptor binding during tolerance and withdrawal to chronic BZ administration

• Animals exhibiting seizure activity during withdrawal showed more apparent changes in AMPA and NMDA binding.

Alcohol and Glutamate• Ethanol potently and selectively inhibits NMDA receptors (NMDARs) and greatly enhances GABAergic neurotransmission through GABA A receptors

• Prolonged ethanol exposure produces a compensatory upregulation of NMDAR functions. These changes are believed to underlie the development of ethanol tolerance and dependence as well as signs of withdrawal.

Summary• Compensatory mechanisms arise in response to enhanced GABAergic inhibition caused by chronic BZ use

• Excitatory mechanisms (i.e., Glutamate) become more sensitive to enhanced GABAergic activity thereby offsetting the balance between excitatory and inhibitory neurotransmission ( tolerance develops)

Summary

Following withdrawal from chronic BZ treatment, the compensatory increase in glutamatergic activity, no longer being balanced by enhanced GABAergic activity, leads to overactivity of glutamate causing withdrawal symptoms such as anxiety, tremors, etc.

Future directions in anxiolytic

pharmacotherapy

• Simultaneous targeting of both 5HT2A (Ritanserin) and 5HT1A receptors could result in robust anxiolytic agents that will have more immediate onset of action than currently available 5HT1A (e.g., Buspirone) receptor acting drugs

• Neuropeptide receptor agonists and antagonists with anxiolytic properties may represent one of the most striking new classes of potential anxiolytic drugs, but this is an emerging field that still requires considerably more systematic clinical testing.

Future directions in anxiolytic

pharmacotherapy

• LY354740 is a potent and selective agonist for group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3 receptors, with anxiolytic activity in several animal models of anxiety

• has been linked to the anxiolytic effects of clinically effective benzodiazepines drugs