Altered Activity of Midbrain Dopamine Neurons Following 7-Day Withdrawal from Chronic Cocaine Abuse is Normalized by D2 Receptor Stimulation During the Early Withdrawal Phase

Abstract

Using in vivo single-unit recording in rats, we compared the effects of continuous cocaine infusion via minipump or single daily injections (both 40 mg/kg/d ϫ 14 days, SC) on the activity of putative dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA).The two opposite behavioral outcomes in animal models of chronic cocaine or amphetamine abuse are sensitization and tolerance, which are induced by intermittent injection or continuous infusion, respectively (Inada et al. 1992;King et al. 1992;Lau et al. 1991;Post and Rose 1976;Reith et al. 1987). Behavioral sensitization has been hypothesized as a model of the increasing reinforcing effects of cocaine in humans, especially during the early stages of abuse (Kilbey and Ellinwood 1977;Post and Contel 1983;Robinson and Berridge 1993;Mendrek et al. 1998;Kalivas 1995). Tolerance, on the other hand, may provide an animal model for elucidating time-dependent loss of mental and physical energy associated with stimulant withdrawal after multi-day high-dose, compulsive binges (Gawin and Ellinwood 1988;Weiss et al. 1995).The two dosing regimens for the above stimulants are also associated with distinctive electrophysiological changes in the potency of dopamine (DA) agonists in inhibiting activity of DA neurons in the substantia nigra zona compacta (SNC, which projects primarily to the dorsal striatum) and ventral tegmental area (VTA, which projects to the ventral striatum and prefrontal cortex). In the SNC, for example, while both continuous (Kamata and Rebec 1984;Ellinwood and Lee 1983;Lee and Ellinwood 1989), the mechanisms underlying this subsensitivity are different (Pitts et al. 1989(Pitts et al. , 1993Lee et al. 1997). For intermittent injections (which lead to phasically high levels of cocaine) an enabling by a D 1 -dependent mechanism appears to play a key role in the agonist subsensitivity (Pitts et al. 1989(Pitts et al. , 1993Lee et al. 1997), whereas a direct change in D 2 autoreceptor sensitivity might underlie the subsensitivity following continuous infusion (Lee et al. 1997). In contrast to the SNC, the findings in the VTA are most consistent with autoreceptor subsensitivity (Henry et al. 1989;Lee et al. 1997;White et al. 1995) and normosensitivity (Lee et al. 1997) 1 day after withdrawal from intermittent and continuous regimens, respectively. The differential effects of chronic cocaine treatments on the VTA and SNC may be reflective of their different afferent connections as well as differences in their respective DA receptor populations.Following a longer withdrawal period (e.g., 7 days), intermittent injections are generally associated with normosensitivity of the SNC and VTA DA neurons to DA agonists (Henry et al. 1989;White et al. 1995;Lee et al. 1997). Continuous infusion is also associated with a normosensitivity of the VTA DA neurons following 7-day withdrawal. However, as we have demonstrated previously, the SNC DA neurons become supersensitive to apomorphine (Ellinwood and Lee 1983;Lee and Ellinwood 1989...

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…Autoreceptor sensitivity has been shown to be altered following chronic exposure to stimulants (Lee et al 1999; Mateo et al 2005; Calipari et al 2014). Here we wanted to assess autoreceptor function in both the NAc core and shell regions following chronic ethanol exposure.…”

Dopamine and addiction: what have we learned from 40 years of research

“…DA neurons population activity is increased (Lee et al 1999;Gao et al 1998). This effect is reversed by blockade and desensitization of D2R, suggesting changes in the function of D2R involved in feedback inhibition in the VTA-NAc pathway (Lee et al 1999;Gao et al 1998).…”

Kappa-Opioid Receptor Signaling in the Striatum as a Potential Modulator of Dopamine Transmission in Cocaine Dependence

“…Decreases in extracellular dopamine levels in the nucleus accumbens have also been reported following cocaine withdrawal (Parsons et al, 1991; Robertson et al, 1991; Rossetti et al, 1992; Weiss et al, 1992). Cocaine administration has also been shown to alter the sensitivity of D2 autoreceptors of the midbrain (Gao et al, 1998; Lee et al, 1999; Marinelli et al, 2003), which could reduce pre-synaptic dopamine release. In addition to these functional changes in dopamine signaling, animal studies have also shown that cocaine exposure produces morphological changes in dopamine neurons.…”