Cocaine self-administration produces a persistent increase in dopamine D2High receptors

Abstract

Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2 High ). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2 High receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2 High receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2 High receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine.

Exposure to Nicotine Produces an Increase in Dopamine D2HighReceptors: A Possible Mechanism for Dopamine Hypersensitivity

“…The increase in D2 High receptors is similar to the increase that has been recently reported by Briand et al (2008) following cocaine self-administration training. It is interesting that the number of nicotine infusions appeared higher in rats that displayed the highest levels of D2 High .…”

“…It has been recently reported that cocaine selfadministration produces a persistent increase in D2 High , a phenomenon that could explain why cocaine administration produces hypersensitivity to dopamine (Briand, Flagel, Seeman, & Robinson, 2008), while drug addicts have a decreased number of striatal dopamine D2 receptors (Volkow et al, 2009). Interestingly, this increase in D2 High has also been reported following amphetamine sensitization (Seeman, Tallerico, Ko, Tenn, & Kapur, 2002), as well as following ethanol, quinpirole, and phencyclidine sensitization (Seeman et al, 2005).…”

Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice

“…D1R mediates reward learning in response to palatable food (Hikida et al, 2010), and targeted loss of D1R decreases operant responding for sucrose (El-Ghundi et al, 2003). Sucrose preference is reduced by D2R antagonism (Hsiao and Smith, 1995), whereas upregulated D2R levels in the NAc have been reported in some rodent studies of repeated cocaine administration (Peris et al, 1990;Maggos et al, 1998;Briand et al, 2008). The elevated D1R and D2R levels observed in this study could thus lead to the increased responsiveness to palatable food and cocaine.…”

Prolonged withdrawal following cocaine self-administration increases resistance to punishment in a cocaine binge

“…This stability is remarkable, given that extended access to cocaine SA produces significant cognitive deficits and impairments in working memory that can persist for at least one month62636465. Such cognitive impairments have also been observed in humans after two weeks of abstinence66.…”