ALTERATIONS IN EXCITATORY AMINO ACID-MEDIATED REGULATION OF MIDBRAIN DOPAMINERGIC-NEURONS INDUCED BY CHRONIC PSYCHOSTIMULANT ADMINISTRATIONAND STRESS - RELEVANCE TO BEHAVIORAL SENSITIZATION AND DRUG-ADDICTION

Repeated, intermittent administration of the psychostimulants d-amphet amine and cocaine, as well as other drugs of abuse, leads to an enduri ng augmentation of certain behavioural responses (e.g. locomotor activ ity) produced by these drugs. This behavioural sensitization has been the subject of considerable Interest due to its potential relevance to drug addiction. Repeated administration of d-amphetamine also leads t o an enhancement in the ability of electrical stimulation of the prefr ontal cortex to induce burst firing in midbrain dopaminergic (DA) neur ones. This hyper-responsiveness probably reflects a potentiation of tr ansmission at excitatory amino acid (EAA)ergic synapses on DA neurones . In addition, we have previously reported that selective activation o f mineralocorticoid receptors (MRs) by corticosterone leads to a poten tiation of EAA-induced burst firing in midbrain DA neurones an effect antagonized by glucocorticoid receptor (GR) activation. In this review article, we propose a model describing how drugs of abuse and stress alter EAA function at the level of DA cells in the ventral tegmental a rea (VTA), which can result in a long-lasting impact on behaviour. D-a mphetamine produces a transitory increase in EAA-mediated transmission at the level of DA cells in the VTA, which triggers a more long-lasti ng change in EAAergic function resembling hippocampal long-term potent iation. Dopaminergic burst events are likely to be a critical link bet ween enhanced EAAergic activity in afferents synapsing on DA neurones and plasticity at these synapses, by increasing calcium transport into the cell, which is known to be an important factor in synaptic plasti city. Selective MR occupation by corticosterone in the VTA facilitates the development of this plasticity. However, we hypothesize that duri ng stress GR-occupation also activates EAAergic afferents to DA neuron es in a manner similar to that following psychostimulants. Under these circumstances, GR-occupation acts via circuitry external to the VTA, which may include the hippocampus. Thus, potentiation of EAAergic syna pses on DA neurones in the VTA may represent a final common pathway by which two divserse means (psychostimulants and stress) achieve the sa me end (sensitization). Alterations in EAA-mediated transmission at th e level of DA calls not only plays a critical role in the induction of behavioural sensitization, but probably continues to produce abnormal DA cell responses in the drug-free situation.