The data presented here demonstrate that behavioral sensitization to amphetamine is attributable, at least in part, to an enhanced mesolimbic DA neuron drive, secondary to augmented activity in the vHipp. This enhanced DA neuron drive is expressed as an increased population activity, i.e. the number of spontaneously active DA neurons. Furthermore, this enhancement is not attributable to the acute pharmacological effects of amphetamine, since acute psychostimulant administration produces the opposite response; i.e., a decrease in the number of spontaneously active DA neurons ( & (Lodge and Grace, 2005
)) due to augmented somatodendritic DA-mediated auto-inhibition and feedback inhibition from forebrain structures (Einhorn et al., 1988
An association between hippocampal activity and ascending DA function has been suggested previously (Legault and Wise, 1999
; Floresco et al., 2001
; Floresco et al., 2003
; Lodge and Grace, 2006a
). Thus, the vHipp can modulate DA neuron population activity and Acb DA overflow via a multisynaptic (vHipp-Acb-ventral pallidal-VTA) pathway (Floresco et al., 2001
; Floresco et al., 2003
). Furthermore NMDA activation of the vHipp augments the locomotor response to intra-Acb amphetamine (White et al., 2006
). We now demonstrate that repeated amphetamine administration can result in aberrant DA neuron signaling and suggest that this is secondary to enhanced activity in the vHipp. Specifically, we demonstrate that repeated amphetamine-treated rats display a significantly higher number of spontaneously active DA neurons compared to control rats, consistent with previous observations (White and Wang, 1984
; Henry et al., 1989
). Such an increase in DA neuron population activity would enhance the tone of the DA system and result in an augmented DA response to subsequent psychostimulant administration. Furthermore, increased DA neuron population activity is also able to regulate phasic DA neuron responses by increasing the number of DA neurons available to convey a phasic signal (Lodge and Grace, 2006a
). Since phasic DA neuron activity is highly correlated with reward prediction (Schultz, 1998
), such an altered phasic signal would likely result in aberrant reward processing.
Given the context-dependant nature of behavioral sensitization and the critical role of the vHipp in the processing of contextual information, we examined whether aberrant hippocampal activity may be responsible for the augmented DA neuron population activity in amphetamine-sensitized rats. Recordings within the vHipp demonstrated that, in amphetamine-sensitized rats, there was a significant increase in baseline activity of the vHipp. Given that the baseline firing rate of vHipp neurons are similar in the awake and anesthetized rats (Jung et al., 1994
), we believe that this 3-fold increase in vHipp activity is sufficient to alter information processing in the Acb. Furthermore, the ability of the mPFC to regulate vHipp-Acb drive was significantly attenuated. Thus, following amphetamine sensitization, the mPFC loses the ability to reset this system to baseline levels. Inactivation of this aberrant vHipp drive via TTX inactivation of the vHipp normalized the increased DA neuron population activity to a level consistently observed in control animals. This manipulation had no significant effect on any other parameter of DA neuron activity in rats repeatedly treated with amphetamine, nor did it have any observable effects on DA neuron activity in control animals. Furthermore, given that chemical enhancement of vHipp output augments the locomotor response to amphetamine (White et al., 2006
) we propose that the behavioral sensitization to repeated amphetamine administration may be attributed to vHipp-induced enhancement of baseline DA neuron population activity. Indeed, bilateral hippocampal inactivation significantly reduced the augmented psychostimulant-induced locomotion observed in amphetamine-treated rats back to that observed in controls, while having no significant effect on amphetamine-induced locomotor activity in control animals. It is important to note that there were no differences in baseline exploratory behavior between the groups and thus the behavioral consequence of the augmented DA neuron activity is only revealed following amphetamine administration.
The model advanced here, that the behavioral sensitization to repeated amphetamine administration may be attributed to vHipp-induced enhancement of baseline DA neuron population activity, is consistent with a number of observations in amphetamine- and/or cocaine-sensitized rats. For example, a number of studies have reported an increased glutamatergic drive in psychostimulant sensitized rats (Karler et al., 1991
; Karler et al., 1994
; Pierce et al., 1996
). Thus, intra-Acb administration of the AMPA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) attenuates the expression of behavioral sensitization to cocaine (Pierce et al., 1996
). Further evidence for an increased glutamatergic tone to the Acb is the observation of altered synaptic morphology in the Acb of sensitized rats. Thus repeated psychostimulant administration induces a robust alteration in the spine density of medium-spiny neurons in the Acb that is localized to the distal dendrites which largely receives extrinsic glutamatergic input (Li et al., 2004
). Consequently we propose that the purported increased glutamatergic drive to the Acb in sensitized rats arises, at least in part, from the ventral hippocampus. Indeed, we now demonstrate that repeated amphetamine administration increases both the average firing rate as well as the pattered activity of vHipp neurons.
The mechanism by which repeated amphetamine administration alters hippocampal output is not clear; however, there is significant evidence demonstrating a critical role of DA in hippocampal transmission. Thus, LTP is an index of synaptic strength and prominent form of signaling in the hippocampus and is strongly dependent on DA. More specifically, late-phase LTP is blocked by dopamine D1 receptor antagonists and is absent in D1 receptor knockout mice, whereas D1 receptor activation leads to an enhancement of hippocampal LTP (Frey et al., 1990
; Frey et al., 1991
; Matthies et al., 1997
; Granado et al., 2008
). As such, it is possible that repeated psychostimulant-induced DA stimulation in the ventral hippocampus of sensitized rats induces an augmented hippocampal output in the form of LTP. Indeed, we have previously demonstrated the occlusion of vHipp-Acb LTP following repeated cocaine administration (Goto and Grace, 2005a
). Interestingly, this effect was not observed following repeated amphetamine administration; rather, LTP was equally induced in amphetamine and saline pretreated animals while the ability of mPFC stimulation to reverse LTP was attenuated.
Taken as a whole, the present study demonstrates that the augmented responsivity to psychomotor stimulants observed in amphetamine-sensitized rats is likely attributable to an increase in tonic DA transmission secondary to augmented activity within the ventral hippocampal. Moreover, an augmentation of vHipp drive was also found in an animal developmental model of schizophrenia, in which endogenous vHipp overdrive also leads to aberrant DA signaling (Lodge and Grace, 2007
). Such an understanding of the functional interactions among these systems and how pathology within these circuits affects central reward processing is critical to gaining a better understanding of the pathophysiology underlying drug abuse, and may provide novel pharmacotherapeutic approaches to its treatment.