RESUMEN El Objetivo general de la presente Tesis Doctoral fue el de estudiar la participación de la neurotransmisión glutamatérgica y del GHB en la adicción a los opiáceos y a la cocaína. En primer lugar hemos pretendido observar la contribución de estos dos sistemas de neurotransmisión en los efectos que la morfina presenta sobre las conductas sociales. Nuestra hipótesis fue que la afectación del sistema glutamatérgico, concretamente bloqueando los receptores NMDA (utilizando Memantina y MK-801) así como la facilitación de la neurotransmisión GABAérgica, mediante la administración de GHB (ácido gammahidroxibutírico) podrían modificar los efectos que sobre las conductas sociales ejerce la morfina. Igualmente nos planteamos estudiar si tanto los síntomas físicos como los motivacionales, medidos mediante el Condicionamiento Aversivo de Lugar (CAL), observados en el síndrome de abstinencia a la morfina, podían verse modificados por las acciones anteriormente mencionadas sobre el sistema glutamatérgico o GABAérgico. También hemos observado el papel del de estos dos sistemas de neurotransmisión sobre las acciones reforzantes de la cocaína. Hemos estudiado el papel sistema glutamatérgico y del GHB sobre los efectos reforzantes de la cocaína, la adquisición, la expresión y el restablecimiento (recaída) mediante el condicionamiento de la preferencia de lugar (CPL) inducido por esta droga. Mediante esta serie de estudios tratamos de explorar el papel de estos sistemas de neurotransmisión tanto en los efectos reforzantes, como en la recaída en el consumo de cocaína. ____________________________________________________________________________________________________

The main aim of the present Doctoral Thesis was to study the participation of the glutamatergic neurotransmission and GHB in the addiction to opiates and cocaine. Firstly, we observed the contribution of these two systems of neurotransmission to the effects that morphine presents on social behaviours. Our hypothesis was that the impairment of the glutamatergic system by blocking the NMDA receptors (using Memantine and MK-801) as well as the facilitation of the GABAergic neurotransmission, by GHB administration (gamma-hydroxybutyric acid) could modify the effects that morphine exerts on social behaviours. Likewise, we studied whether the physical as well as the motivational symptoms, measured by means of Conditioned Place Aversion (CPA), observed in the morphine wtihdrawal syndrome, could be modified by the previously mentioned actions on the glutamatergic or GABAergic systems. We have also studied the role of these two neurotransmission systems in the rewarding actions of cocaine. We examined the influence of the glutamatergic system and GHB on the acquisition, expression and reinstatement (relapse) of the cocaine-induced conditioned place preference (CPP). With these studies we explored the role of these neurotransmission systems in the cocaine-rewarding effects and the relapse to cocaine consumption. Our results show that memantine administration significantly increased motor activity without modifiying the antiaggressive effect of morphine. Memantine blocked the physical and motivational symptoms of the morphine withdrawal, whereas MK-801 was more effective in blocking only the motivational symptoms of this withdrawal syndrome evaluated by the CPA procedure. On the other hand, we could observe that GHB potentiates morphine-induced effects on social behaviours, counteracting the hyperactivity induced by this opiate, and ameliorating the physical as well as motivational aspects of the morphine withdrawal syndrome. In addition, we have observed that GHB has no synergic action on the rewarding effects of cocaine, evaluated by the CPP procedure, It blocked the cocaine-seeking behaviour (relapse) when it was administered during the acquisition or the expression of the conditioning or with a priming dose of cocaine. Also we have observed that NMDA and AMPA receptors blockaded by memantine and CNQX administration prevented the acquisition and expression of cocaine-induced CPP but did not show the ability to block the relapse induced by priming administration of this same drug. The present study indicates that glutamatergic neurotransmission plays an important role in the establishment of morphine dependency, as is observed by the reduction of the physical and motivational signs in the morphine withdrawal after the administration of NMDA receptor blockers. Our results also indicate a clear interaction between the opiate and GABAergic systems, since GHB (a GABA metabolite) interacts with morphine, having an additive effect on morphine-affected social behaviours but counteracting morphine-induced increases in motor activity. We have confirmed that GHB is a useful tool capable of ameliorating both the physical as well as motivational aspects of opiate witdrawal. Also we verified that the relapse in cocaine-seeking behaviour could be blocked by GHB when administered during the acquisition of the conditioning procedure, the expression, or even, jointly with a priming dose of cocaine. Finally, the glutamatergic system also plays a role in the acquisition and expression of the cocaine-induced CPP, but not so in the reinstatement of this preference by a priming dose of cocaine. Our results can help to better understand the underlying neurobiological phenomena in the drugs addictive behaviour and the possible use of memantine and GHB in the treatment of addiction, suggesting their importance as therapeutic tools in the addiction to opiates and psychoestimulants (cocaine).