The effect of dopamine receptor blockade in the rodent nucleus accumbens on local field potential oscillations and motor activity in response to ketamine

Abstract

Altered functioning of the nucleus accumbens (NAc) has been implicated in the psychotomimetic actions of NMDA receptor (NMDAR) antagonists and the pathophysiology of schizophrenia. We have shown previously that NMDAR antagonists enhance the power of high-frequency oscillations (HFO) in the NAc in a dose-dependent manner, as well as increase locomotor activity. Systemic administration of NMDAR antagonists is known to increase the release of dopamine in the NAc and dopamine antagonists can reduce ketamine-induced hyperactivity. In this study, we examined the effect of 0.5 μl intra-NAc infusion of 3.2 μg SCH23390 (D1 antagonist), 10 μg raclopride (D2 antagonist) and saline on ketamine-induced changes in motor and oscillatory activity. We found that local blockade of D1 receptors attenuated ketamine-induced increases in motor activity and blockade of D2 receptors produced a much weaker effect, with respect to saline-infused control groups. In contrast, none of the antagonists, infused separately or together, significantly modified the power or dominant frequency of ketamine-induced increases in HFO, but changes in delta and theta frequency bands were observed. Together, these findings suggest, that, in contrast to delta and theta frequency bands, the generation of ketamine enhanced-HFO in the NAc is not causally related to locomotor activation and occurs largely independently of local changes in dopamine receptor activation.

Introduction

The nucleus accumbens (NAc) receives excitatory glutamatergic inputs from the prefrontal cortex, hippocampus and basolateral amygdala, as well as a dense dopaminergic projection from the ventral tegmental area (Newman & Winans, 1980, Voorn et al., 1986, Christie et al., 1987, Finch, 1996). The NAc is considered to integrate afferent inputs and provide appropriate motor responses (Mogenson et al., 1980). Neurons of the NAc express D1 and D2 receptor classes. Numerous studies have demonstrated that dopamine can modulate excitatory inputs to the NAc by both classes of receptor (for reviews see Nicola et al., 2000, O'Donnell et al., 1999). In particular, recently, it has been shown that D1 and D2 receptors, differentially modulate hippocampal and cortical input, respectively (Goto and Grace, 2005). A failure of the NAc to properly integrate afferent signals has been proposed to underlie certain features of psychiatric disorders (Grace, 2000), as well as, some of the psychotomimetic effects of drugs of abuse.

NMDA receptor antagonists, such as ketamine, are a class of compound that produce a transient “schizophrenia-like” state in humans (Krystal et al., 2003) and have been shown to produce behavioural hyperactivity, social interaction and impairments in learning and memory in rodents (Sams-Dodd, 1998, Tiedtke et al., 1990, Steinpreis et al., 1994, Verma & Moghaddam, 1996). Dopamine, which has long been considered important in the pathophysiology of schizophrenia, also appears to be a critical neurotransmitter mediating the effects of NMDA receptor antagonists. For example, NMDA receptor antagonists provoke large increases in dopamine and to a lesser extent glutamate release in the NAc and medial prefrontal cortex, which almost certainly contribute to a breakdown in normal information processing (Adams & Moghaddam, 1998, Steinpreis & Salamone, 1993, Bubser et al., 1992). Systemic administration of dopamine antagonists and lesions of dopamine projections to the NAc also reduce some of the locomotor stimulatory effects of NMDA receptor antagonists (French, 1986, Ouagazzal et al., 1993, Ouagazzal et al., 1994, Yamamoto et al., 1997). Additionally, local infusion of dopamine antagonists can reduce locomotor stimulation produced by MK801 (Ouagazzal & Amalric, 1995, Willins et al., 1993). However, there is also evidence that glutamatergic hyperstimulation may better account for some of the behavioural effects produced by NMDA receptor antagonists (Adams and Moghaddam, 1998).

While many advances have been made in recent years to elucidate the complex neurophysiology of the NAc (for review see Goto and Grace, 2008), the mechanisms underlying the effects of NMDA receptor antagonists in this structure are only partially understood. We have shown previously, that both systemic and intra-NAc administration of NMDA receptor antagonists modifies oscillatory activity (Hunt et al., 2006, Hunt et al., 2010). Ketamine-induced increases in the power of high frequency oscillations (HFO) broadly correlate with motor activation and we have found partial reversal of aberrant oscillatory activity with lamotrigine, a drug that can reduce some of the neuropsychiatric effects of ketamine in humans and rats (Hunt et al., 2008). However, to date, the potential modulatory role of dopamine on the increases HFO power produced by ketamine is unknown. Considering the importance of dopamine on neuronal signaling and motor activation, the aim of the present study was to examine the effect of dopamine blockade on ketamine-induced changes in locomotor activity and oscillatory activity, using selective SCH23390 (D1 antagonist) and raclopride (D2 antagonist), locally infused to the NAc.