Ventral Striatum: Incentive Salience Pathways, Salience Attribution

Another plasticity associated with behavioral sensitization is a persistent potentiation of nucleus accumbens excitatory synapses that is observed after repeated drug exposure followed by an extended drug-free period (Kourrich et al, 2007). Repeated cocaine administration increases glutamate neurotransmission only in rats that showed behavioral sensitization (Pierce et al, 1996). In addition, cocaine-sensitized mice showed an enhancement of LTP in nucleus accumbens slices during withdrawal, presumably reflecting increased activity of glutamatergic activity (Yao et al, 2004). An increased surface-to-intracellular ratio of glutamate-1 receptors (GluR1) has been observed 21 days after the last injection of cocaine, suggesting a slowly developing redistribution of AMPA receptors to the surface of nucleus accumbens neurons, particularly in those lacking GluR2 (Boudreau and Wolf, 2005; Conrad et al, 2008). The increases in cell-surface AMPA receptors depends on activation of dopamine D₁ receptors and subsequent protein kinase A signaling (Chao et al, 2002). Functionally, overexpression of GluR1 in the nucleus accumbens facilitated extinction of cocaine-seeking responses (Sutton et al, 2003) and increased brain stimulation reward thresholds, reflecting decreased reward and possibly decreased motivated behavior (Todtenkopf et al, 2006). However, a single reexposure to cocaine during extended withdrawal produced synaptic depression, which may reflect the enhanced glutamate release during cocaine reexposure (Kourrich et al, 2007). Curiously, the increase in AMPA receptor expression observed with cocaine does not occur in amphetamine-sensitized rats, leading to the hypothesis of different functional effects of glutamate projections to the nucleus accumbens during cocaine vs amphetamine withdrawal (Nelson et al, 2009).

Consistent with the results of altered glutamate neurotransmission in cocaine-sensitized rats, microdialysis and microinjection studies have shown that following chronic cocaine, decreased basal release of glutamate occurs but sensitized synaptic glutamate release during reinstatement of extinguished drug-seeking in rats (Kalivas and O'Brien, 2008; McFarland et al, 2003). This glutamate dysregulation has been hypothesized to be caused by decreased function of the cystine?glutamate exchanger (Baker et al, 2003) and desensitization of the metabotropic glutamate mGlu2/3 receptor. Lower basal levels of glutamate, combined with increased release of synaptic glutamate from activation of prefrontal cortex afferents to the nucleus accumbens, are hypothesized to result in a drive to engage in drug-seeking (Kalivas, 2004).

These long-lasting synaptic effects produce both a decrease in glutamate neurotransmission during chronic administration of the drug and a persistent increase in the efficacy of glutamatergic synaptic neurotransmission during reinstatement following withdrawal. These dynamic changes may promote cellular excitation, which has been hypothesized to be an important substrate for sensitization and drug-related learning in the addictive state (Kauer and Malenka, 2007; Wolf et al, 2004).

As previously suggested by animal models, the magnitude of striatal dopamine release (particularly in its ventral aspect) in humans correlates positively with the hedonic response to most drugs of abuse, including amphetamine (Drevets et al, 2001), cocaine (Volkow et al, 1997a), methylphenidate (Volkow et al, 2002), and nicotine (Sharma and Brody, 2009). The drug-dependent, fast, and supraphysiological increases in dopamine are likely to mimic the dopamine changes induced by the phasic dopamine cell firing that occurs in response to salient stimuli, thus categorizing the drug experience as one that is highly salient, an experiential outcome that commands attention and promotes arousal, conditioned learning, and motivation (Volkow et al, 2004b). On the basis of findings in laboratory animals, the frequent exposure to these drug responses in drug abusers is postulated to result in the recalibration of dopamine-activating (reward) thresholds for natural reinforcers.

Thus, one can envision the development of a change in firing in mesolimbic dopamine neurons that begins with one administration of the drug, develops into LTP first in the VTA then nucleus accumbens, and via feedback loops subsequently engages the dorsal striatum. Moreover, long-term changes in the CeA and medial prefrontal cortex may follow, and combined with dysregulation of the brain stress systems (see below) may provide a powerful drive for drug-seeking behavior even months after drug withdrawal (Figure 4 and ​and55).

Date: 2016-06-12; view: 239