The neurobiology of motivation: Double dissociation of motivational effects under deprivation versus non-deprivation conditions

Motivational constructs were developed in psychology in order to account for some of the variability that we observe in the behavior of organisms. This thesis is designed to reveal some critical neuroanatomical and pharmacological substrates involved in motivational events that occur under conditions of deprivation versus non deprivation. The aim is to identify the neural substrates serving motivational roles and dissociate those motivational events that derive from distinct brain mechanisms. Initially, I used opiates instead of food or water to generate motivational states. I sought to find at first a critical neural substrate that underlies opiate motivation, at least in the drug naive state. Subsequently, I asked whether the motivational effects of opiates in the drug dependent state derive from the same brain mechanisms as those mechanisms underlying motivational effects in the drug naive state. After studying the neurobiological basis of opiate motivation in the drug naive versus drug dependent states, I studied the relevance of the motivational mechanisms underlying the motivation for opiates to those mechanisms subserving more traditional motivational functions such as the motivation for food.;I found a critical role for a midbrain output region of the limbic system, the tegmental pedunculopontine nucleus (TPP), in specifically the motivational effects produced by opiates in drug naive animals. Bilateral ibotenic acid lesions of the TPP abolished the conditioned place preferences produced by even very high doses of morphine in drug naive animals. Identical lesions failed to attenuate the preferences produced by morphine in physically dependent animals. These TPP lesion effects were behaviorally specific in that the locomotor excitatory effects of morphine were blocked by the lesions, but the analgesic and the cataleptic effects of morphine were not affected by TPP lesions. Although TPP lesions blocked opiate motivation in drug naive, but not drug dependent, animals, I found that the function of dopamine neurons is critical for opiate motivation in drug dependent, but not drug naive, animals. Indeed, neuroleptics (dopamine antagonists) blocked the conditioned place preferences produced with morphine and heroin in dependent animals, but not the conditioned place preferences produced with similar doses of the opiates in drug naive animals. An identical set of experiments where food was substituted for opiates, and food deprivation or physical dependence and withdrawal, revealed that the TPP region is critical for food motivation in the sated (non food deprived), but not in the food deprived state. In contrast, the function of dopamine neurons was critical for food motivation in the food deprived, but not in the food sated state. I propose that psychoactive drugs exert their motivational impact through activation of neural mechanisms that evolved in order to subserve natural motivational functions. Furthermore, rewarding stimuli exert motivational effects through activation of two parallel mechanisms in the nervous system: a circuit through the TPP that mediates non deprivation induced mechanisms of motivation, and an independent circuitry through dopamine neurons subserving motivational mechanisms associated with deprivation and homeostatic drives.