Addict Biol. 2017 Mar;22(2):446-456. doi: 10.1111/adb.12345.

Cocaine self-administration induces changes in synaptic transmission and plasticity in ventral hippocampus.




Scientific pursuit behind the euphoria and craving due to initial substance abuse and resulting long-term addiction, have, for decades, focused on specific acute and direct responses in various regions of the brain. To date there is, at least when it comes to the initial stages of addiction, consensus among the regions of the brain and neural circuitry involved. It is also generally acknowledged that commonly abused drugs not only render the initial euphoric sensation, but also will make certain regions sensitive to stress and negative moods. Yet, despite intensive investigations carried out over decades, many unanswered questions remain in the field of addiction such as how the phenomenon of escalation in drug use occurs; and probably more importantly, why many people find permanent abstention from drugs particularly difficult. It seems that, we’ve started seeing the light at the end of the tunnel in this conundrum.


More recently, Keralapurath et al., a team from Dept. of Physiology & Pharmacology, University of Georgia, have examined in greater detail, the role of the hippocampus, the brain’s memory structure, in the context of drug abuse; and their findings have thrown crucial light on several important factors which could be pivotal in the effective treatment of drug addiction.


Historically, because it appeared that this memory region of the brain was not directly involved in the commencement of addiction, it received precious little attention by way of investigation. However, in the last decade or so, functional heterogeneity between the dorsal and ventral sectors (regions) of hippocampus is widely acknowledged: dorsal sector mainly involved in cognitive and spatial information processing, while the ventral sector particularly being active in processing emotions. The studies conducted by Keralapurath et al., to find the changes induced by cocaine, a widely abused psychostimulant, in the hippocampus, has provided information which may yield many important answers, or at least stimulate further investigation, into one of the most confounding aspects of drug addiction – that of relapse behavior even after long periods of abstinence.


Dr. John Wagner, the principal investigator of the study, and his lab at The University of Georgia, are at the forefront in pursuing explanations for how and why the parts of the brain involved in learning and memory, are critical in various stages of drug abuse and ultimately culminating in typical addictive pathology. Their research led them to specifically examine the effects of cocaine on hippocampal synaptic plasticity in vivo and ex vivo and in particular the expression of long-term potentiation (LTP) in the CA1 region of the structure. Synaptic plasticity is widely recognized as the phenomenon by which neuronal connections are changed to adapt to various external stimuli. Two common mechanisms by which synaptic plasticity is occurring are, long-term potentiation (LTP) and long-term depression (LTD), where in neuronal connections are made stronger or weaker, respectively, resulting in either learning or forgetting. Neural plasticity has certainly received much attention in the context of drug use, and as a consequence the way, or ways, in which specific drugs alter synaptic plasticity in the ‘reward pathways’ of brain (involving regions such as nucleus accumbens, ventral tegmental area etc.), causing the initial ‘euphoria’ or ‘high’ experienced by the drug addicts.


Keralapurath et al., exposed the rats to cocaine via, a) passive mode, where the drug was administered daily by intraperitoneal injections for 5 days, and b) rats were trained to self-administer cocaine for as long as 6hrs/day for 3 weeks. In response to a challenge dose of cocaine 1 week later, the first group of rats showed increased locomotor activity, a behavioural feature widely recognised to occur when the animals get sensitized to cocaine. In the second group, during the course of self-administration, rats showed typical addiction attributes such as, binging and escalation of drug intake. Later, using electrophysiological techniques, they recorded neuronal transmission and plasticity properties in the hippocampal slices prepared from both the dorsal and ventral sectors of hippocampus from both passive (measured 1 week after the final dose) and self-administration (measured 1month later after the final exposure) groups. In both the groups, cocaine was found to selectively target the ventral hippocampal neural circuitry, by altering the baseline neurotransmission &/or LTP expression, whilst failing to produce effects in the dorsal hippocampal sector.


Specifically, passive mode of cocaine exposures acted as ‘soft’ ‘metaplastic’ triggers by priming (preparing) the neural circuitry in the animals, however without any apparent changes to the basal neurotransmission, for an altered LTP expression when tested later in the hippocampal slices. (Metaplasticity, which is sometimes referred to as ‘plasticity of plasticity’ differs from the conventional because of the way in which persistent changes are made in how neurons respond to experiences not only in the present but also into the future. The phenomenon is a bit complicated because it often occurs without any identifiable changes to the baseline synaptic transmission, and so only becomes apparent when further triggers are generated). However, in rats which were allowed to self-administer, cocaine episodes potentially acted as triggers ‘strong’ enough to alter the baseline synaptic transmission and more surprisingly, masked the expression of LTP when tested later in the slices.


Although previous studies were suggestive of the hippocampal role in addiction and the triggering of associated memories, this is the first study which shows persistent plasticity changes in the CA1 region of the ventral sector.


By narrowing investigations to this specific region it can be shown with reasonable certainty that cocaine-induced metaplasticity in the ventral hippocampus may lead to an ongoing potentiated state which contributes to primed (via external triggers such as stress, context, cues or the drug itself) reinstatement of drug-seeking behavior.


However, one factor which can often skew studies investigating not only cocaine usage but also other addictions and subsequent relapse, is that of environmental stress which can produce similar changes to the same region of the brain. This made it necessary to not only provide controls which were subjected to stress but also to isolate any potential stress triggers in the study group. Both acute and chronic stressors have been shown to negatively impact hippocampal learning and synaptic properties, and although the effects of minor, intermittent stressors (which approximate to daily life stressors in humans) are not well studied.


The research team investigated the effects of minor stressors in rats such as novelty, handling and intraperitoneal injections associated with a locomotor sensitization protocol on the hippocampal synaptic plasticity. Their findings revealed that persistent metaplastic changes were observed specifically in the ventral hippocampus due to these stressors. This suggests that minor stressors could somehow prime the ventral hippocampal circuit to express aberrant responses toward future stimuli (such as drug episodes).


Their work also contributed to our understanding of the brain by strengthening conclusions relating to previous, yet distinct, research which investigated the specific and distinct roles played by these regions of the hippocampus. Previously it had been strongly suggested that the vH sector is predominantly involved in various affective behaviors including, anxiety, fear, excitability and reinstatement of reward, whereas the dH was thought to influence cognitive performance, exploration and spatial navigation.


The results produced by MK et al went toward supporting these findings and further strengthened the idea that changes which arise in the vH are more significant in respect of substance abuse than those in the dH and consequently the suggestion is that the vH plays a potentially epicentric role in drug use similar stress comorbidities.


The implications of the conclusions are clear in that reinstatement of drug abuse is a major obstacle to be overcome when treating users of illegal substances, and the revelation that specific areas of the brain have been molded to respond to specific triggers which result in reinstatement could have great impact on the treatment of substance abusers in the future.