of GABA. This results in dopamine release in the nucleus accumbens and hippocampus. Opioid receptor agonists increase extracellular dopamine levels within the nucleus accumbens by disinhibiting GABA interneurons in the VTA (Johnson and North, 1992). Benzodiazepines and barbiturates affect GABA receptor function, and may also act in the GABAergic circuitry that is efferent to the mesolimbic DS (Wise, 1998). Benzodiazepines increase stimulation of certain GABAA receptors in inhibitory interneurons in the VTA, which increases dopaminergic VTA excitability (Tan et al., 2010). Mice without the metabotropic glutamate receptor mGluR5 are unresponsive to cocaine (Nestler, 2001). Glutamate (NMDA) receptor function depends on the phosphorylation of CREB, a transcription factor (Das et al., 1997; Konradi et al., 1996), which is mediated by the D1 dopamine receptors. Sensitization by drugs of abuse may be facilitated by a glutamate–dopamine interaction caused when drugs are administered in a novel environment (Uslaner et al., 2001). Glutamate, via induction of the AMPA glutamate receptor GluR2 subunit in the nucleus accumbens, appears to mediate the function of another transcription factor, ΔFosB (Kelz et al., 1999). The latter has been termed a “molecular switch for addiction,” as it parallels sensitization to drugs (Nestler, 2001), and is generally an important component
